Aminopyrimidine kinase inhibitors

ABSTRACT

Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of CK1, CK1γ1, CK1γ2, CK1γ3, CK2, Pim 1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, the AKT pathway, and/or the mTOR pathway. Uses are also disclosed for the treatment or prevention of a range of therapeutic indications due at least in part to aberrant physiological activity of CK1, CK1γ1, CK1γ2, CK1γ3, CK2, Pim 1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, the AKT pathway, and/or the mTOR pathway.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 13/659,343 filed Oct. 24, 2012, which claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 61/555,617, filed Nov. 4, 2011.

BACKGROUND OF THE INVENTION

Casein kinase 1 (CK1) is a family of evolutionarily conserved serine/threonine kinases including seven known members in vertebrates (CK1α, -β, -γ1, -γ2, -γ3, -δ and -ε). The CK1s contain a typical kinase domain followed by a C-terminal tail region, which has been implicated in the regulation of CK1 localization, substrate selectivity and kinase activity. Myriad proteins have been found to be phosphorylated by CK1s, which are involved in a wide range of cellular functions including vesicular trafficking, DNA damage repair, cell cycle progression, cytokinesis and circadian rhythms (reviewed by Gross and Anderson (1998) Cell Signal 10:699-711; Vielhaber and Virshup (2001) IUBMB Life 51:73-8; Knippschild et al. (2005) Cell Signal 17:675-89). Moreover, CK1 family members (-α, -δ/ε and -γ) modulate the activities of major signaling pathways (for example, Wnt and Shh) through several mechanisms (Peters et al. (1999) Nature 401:345-50; Liu et al. (2002); Price and Kalderon (2002) Cell 108:823-35; Davidson et al. (2005) Nature 438:867-72; Zeng et al. (2005) Nature 438:873-7; and reviewed by Price (2006) Genes Dev 20:399-410).

In mammals seven CK1 isoforms, namely CK1α, β, γ₁₋₃, δ and ε, and several splice variants have been described. They all contain a highly conserved kinase domain, a short N-terminal domain of 6 to 76 amino acids and a highly variable C-terminal domain of 24 to more than 200 amino acids. The constitutive phosphotransferase activity of CK1 isoforms is tightly controlled by several mechanisms. For example, the closely related isoforms CK1δ and ε, which share a 98% identity at the amino acid level in their catalytic domain, are regulated by autophosphorylation, dephosphorylation and proteolytic cleavage. Members of the CK1 family are found in the nucleus, the cytoplasm and in the plasma membrane. By phosphorylating many different substrates bearing either a canonical or non-canonical consensus sequence they modulate the activity of key regulator proteins involved in many cellular processes such as cell differentiation, cell proliferation, apoptosis, circadian rhythm, chromosome segregation, and vesicle transport.

The Pim kinase family contains three isoforms, Pim-1, Pim-2 and Pim-3, and has recently emerged as targets of interest in oncology and immune regulation. Ongoing studies have identified a role for these proteins in cell survival and proliferation, both functionally and mechanistically, and overexpression has been observed in a number of human cancers and inflammatory states.

Pim kinases suppress apoptosis and regulate cell-cycle progression. Elevated levels of Pim kinases have been reported in solid tumors such as prostate cancer and pancreatic cancer. Pim-1 was initially discovered in murine leukemia and several independent studies have shown this kinase to be upregulated in human prostate cancer. Pim-1, 2 and 3 make up a distinct and highly homologous family of serine/threonine kinases belonging to the calmodulin-dependent protein kinase-related (CAMK) family. In addition to the three gene-encoded proteins, translational variants have also been reported for Pim-1 and 2 resulting from utilization of alternative start codons. The name Pim refers to the original identification of the pim-1 gene as a frequent proviral insertion site in Moloney murine leukemia virus-induced T-cell lymphomas, and the gene encoding Pim-2 was subsequently found to have similar susceptibility. Pim-3, originally designated kinase induced by depolarization (KID)-1, was later renamed due to high sequence similarity to Pim-1 (71% identity at the amino acid level). Considering all three isoforms, Pim proteins are widely expressed with high levels in hematopoietic tissue and are aberrantly expressed in a variety of human malignancies. Pim kinases positively regulate cell survival and proliferation, affording therapeutic opportunities in oncology. The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma. A role has been described for Pim-1 in human pancreatic ductal adenocarcinoma (PDAC), and Pim-1 kinase has been identified as a potential molecular marker for mutated K-Ras activity. Pim-2 is rapidly becoming an increasingly interesting target for multiple myeloma. Rapamycin combined with Pim-2 silencing, or Pim inhibitors combined with PI3K inhibitors have been found to cooperatively enhance multiple myeloma cell death, suggesting independent pathways with common substrates. Further, it has been shown that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy.

A role for Pim kinases in immune regulation has also been observed. Pim-2 has been reported to have enhanced levels of expression in a variety of inflammatory states and may function as a positive regulator of interleukin-6 (IL-6), whereby overexpression of the kinase augments stimulus-induced IL-6 levels. Pim-1 and 2 have also been implicated in cytokine-induced T-cell growth and survival. Comparing the sensitivity of stimulated T cells from Pim-1−/− Pim-2−/− mice to wild-type mice following treatment with the immunosuppressant rapamycin, it was found that T-cell activation was significantly impaired by Pim-1/Pim-2 deficiency, suggesting that Pim kinases promote lymphocyte growth and survival through a PI3K/AKT (PKB, protein kinase B)/mammalian target of rapamycin (mTOR)-independent pathway. Other parallel but independent functions and overlapping substrate specificity for proteins in these pathways have been reported as well, including the positive regulation of transcription of nuclear factor kappa-B (NF-κB)-responsive genes, which have implications in both inflammation and oncology. Therefore, Pim kinases are attractive targets for both therapeutic areas. Further, Pim kinases have been reported to play a role in the protection of the ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp; ABCB1) from proteolytic and proteasomal degradation. Pgp is known to mediate drug efflux and as such, inhibitors of Pim kinases may provide a novel approach to abrogating drug resistance.

SUMMARY OF THE INVENTION

An aspect of the present invention relates to compounds that inhibit casein kinase 1 and/or casein kinase 2 and/or a PIM kinase. For example, an embodiment relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃—R₆;     -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;     -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,         —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R₅ is selected from the group consisting of 1,4-cyclohexanediyl,         1,4-phenylene, 1,4-cycloheptanediyl, 1,4-cyclooctanediyl,         1,5-cyclooctanediyl, 1,4-bicyclo[2.2.1]heptanediyl,         1,4-bicyclo[2.2.2]octanediyl, and 1,5-bicyclo[3.3.1]nonanediyl;     -   R₆ is selected from the group consisting of alkyl, alkylaryl,         aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of         which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of alkyl, alkylaryl, aralkyl, aryl, heteroaryl,         alkoxy, hydroxy, perfluoroalkyl, trifluoromethoxy, and halide,         wherein the optional aryl or heteroaryl substituent may be         optionally substituted with alkyl, halide, alkoxy,         perfluoroalkyl, or dioxolanyl;     -   R₇ is selected from the group consisting of H, —C(═NR)R,         —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl,         alkylheteroalkyl, and heteroaryl, any of which is optionally         mono or di-substituted, and the substituents, if present, are         independently selected from the group consisting of alkyl,         alkylaryl, aralkyl, aryl, heteroaryl, alkoxy, hydroxy,         perfluoroalkyl, trifluoromethoxy, and halide, wherein the         optional aryl or heteroaryl substituent may be optionally         substituted with alkyl, halide, alkoxy, perfluoroalkyl, or         dioxolanyl, or     -   two instances of R₇ and the nitrogen to which they are bonded         taken together represent a nitrogen-containing heterocyclyl,         optionally containing one additional heteroatom in the ring,         wherein said additional heteroatom is selected from the group         consisting of —O—, —N(R)—, and —S—;     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl;     -   R is H or (C₁-C₄)alkyl; and     -   n is 1, 2 or 3.

One aspect of the invention is a compound of formula 2 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃—R₄;     -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;     -   R₁ is selected from the group consisting of 1,4-cyclohexanediyl         and 1,4-phenylene;     -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈, —(C═O)OCHR₈O(C═O)CH₃,         or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R₄ is selected from the group consisting of aryl and heteroaryl,         either of which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of halide, alkyl, perfluoroalkyl, aryl,         heteroaryl, and heterocyclyl; wherein the optional aryl or         heteroaryl substituent is itself optionally substituted with         perfluoroalkyl or dioxolane;     -   R₇ is selected from the group consisting of H, —C(═NR)R,         —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl,         alkylheteroalkyl, and heteroaryl, any of which is optionally         mono or di-substituted, and the substituents, if present, are         independently selected from the group consisting of alkyl,         alkylaryl, aralkyl (including but not limited to benzyl), aryl         (including but not limited to phenyl), heteroaryl (including but         not limited to pyridyl, imidazolyl, thiazolyl, furyl, and         thionyl), alkoxy (including but not limited to methoxy),         hydroxy, perfluoroalkyl (including but not limited to         trifluoromethyl), trifluoromethoxy, and halide (including but         not limited to fluoride and chloride), wherein the optional aryl         or heteroaryl substituent may be optionally substituted with         alkyl, halide, alkoxy, perfluoroalkyl, or dioxolanyl, or     -   two instances of R₇ and the nitrogen to which they are bonded         taken together represent a nitrogen-containing heterocyclyl,         optionally containing one additional heteroatom in the ring,         wherein said additional heteroatom is selected from the group         consisting of —O—, —N(R)—, and —S—;     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl;     -   R is H or (C₁-C₄)alkyl; and     -   n is 1, 2 or 3.

Another embodiment relates to a compound of formula 3 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,         —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R is H or (C₁-C₄)alkyl;     -   n is 1, 2 or 3;     -   R₆ is selected from the group consisting of alkyl, alkylaryl,         aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of         which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of alkyl, alkylaryl, aralkyl (including but not         limited to benzyl), aryl (including but not limited to phenyl),         heteroaryl (including but not limited to pyridyl, imidazolyl,         thiazolyl, furyl, and thionyl), alkoxy (including but not         limited to methoxy), hydroxy, perfluoroalkyl (including but not         limited to trifluoromethyl), trifluoromethoxy, and halide         (including but not limited to fluoride and chloride), wherein         the optional aryl or heteroaryl substituent may be optionally         substituted with alkyl, halide, alkoxy, perfluoroalkyl, or         dioxolanyl; and     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

Another embodiment relates to a compound of formula 4 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R is H or (C₁-C₄)alkyl;     -   n is 1, 2 or 3; and     -   R₄ is selected from the group consisting of aryl and heteroaryl,         either of which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of halide, alkyl, perfluoroalkyl, aryl,         heteroaryl, and heterocyclyl; wherein the optional aryl or         heteroaryl substituent is itself optionally substituted with         perfluoroalkyl or dioxolane.

Another embodiment relates to a compound of formula 5 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;     -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,         —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R is H or (C₁-C₄)alkyl;     -   n is 1, 2 or 3;     -   R₆ is selected from the group consisting of alkyl, alkylaryl,         aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of         which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of alkyl, alkylaryl, aralkyl (including but not         limited to benzyl), aryl (including but not limited to phenyl),         heteroaryl (including but not limited to pyridyl, imidazolyl,         thiazolyl, furyl, and thionyl), alkoxy (including but not         limited to methoxy), hydroxy, perfluoroalkyl (including but not         limited to trifluoromethyl), trifluoromethoxy, and halide         (including but not limited to fluoride and chloride), wherein         the optional aryl or heteroaryl substituent may be optionally         substituted with alkyl, halide, alkoxy, perfluoroalkyl, or         dioxolanyl; and     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

Another embodiment relates to a compound of formula 6 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;     -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,         —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R is H or (C₁-C₄)alkyl;     -   n is 1, 2 or 3;     -   R₆ is selected from the group consisting of alkyl, alkylaryl,         aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of         which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of alkyl, alkylaryl, aralkyl (including but not         limited to benzyl), aryl (including but not limited to phenyl),         heteroaryl (including but not limited to pyridyl, imidazolyl,         thiazolyl, furyl, and thionyl), alkoxy (including but not         limited to methoxy), hydroxy, perfluoroalkyl (including but not         limited to trifluoromethyl), trifluoromethoxy, and halide         (including but not limited to fluoride and chloride), wherein         the optional aryl or heteroaryl substituent may be optionally         substituted with alkyl, halide, alkoxy, perfluoroalkyl, or         dioxolanyl; and     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC₅₀ of less than about 5000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC₅₀ of less than about 1000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC₅₀ of less than about 500 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of CK2. In one embodiment the compound has an IC₅₀ of less than about 5000 nM for CK2. In one embodiment the compound has an IC₅₀ of less than about 1000 nM for CK2. In one embodiment the compound has an IC₅₀ of less than about 500 nM for CK2.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of PIM1, PIM2, or PIM3. In one embodiment the compound has an IC₅₀ of less than about 5000 nM for PIM1, PIM2, or PIM3. In one embodiment the compound has an IC₅₀ of less than about 1000 nM for PIM1, PIM2, or PIM3. In one embodiment the compound has an IC₅₀ of less than about 500 nM for PIM1, PIM2, or PIM3.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the Wnt pathway.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the TGFβ pathway.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the JAK/STAT pathway.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the mTOR pathway.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is an inhibitor of the AKT pathway.

An embodiment relates to any one of the aforementioned compounds, wherein the compound is a modulator of Pgp degradation, drug efflux, or drug resistance.

An embodiment relates to a pharmaceutical composition comprising any one or combination of the aforementioned compounds, and a pharmaceutically acceptable carrier.

Another embodiment relates to a method of inhibiting CK1 activity, comprising contacting CK1, CK1γ1, CK1γ2, or CK1γ3 with any one of the aforementioned compounds.

Another embodiment relates to a method of inhibiting CK2 activity, comprising contacting CK2 with any one of the aforementioned compounds.

Another embodiment relates to a method of treating or preventing a condition associated with aberrant CK1, CK1γ1, CK1γ2, or CK1γ3 activity, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating or preventing a condition associated with aberrant CK2 activity, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds or pharmaceutical compositions. In one embodiment the cancer is a cancer of a system selected from the group consisting of the hematopoietic system, immune system, endocrine system, pulmonary system, gastrointestinal system, musculoskeletal system, reproductive system, central nervous system, and urologic system. In one embodiment the cancer is located in the mammal's myeloid tissues, lymphoid tissues, pancreatic tissues, thyroid tissues, lung tissues, colon tissues, rectal tissues, anal tissues, liver tissues, skin, bone, ovarian tissues, uterine tissues, cervical tissues, breast, prostate, testicular tissues, brain, brainstem, meningeal tissues, kidney or bladder. In one embodiment the cancer is selected from the group consisting of breast cancer, colon cancer, multiple myeloma, prostate cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, hematologic malignancy, renal cell carcinoma, renal cancer, malignant melanoma, pancreatic cancer, lung cancer, colorectal carcinoma, brain cancer, head and neck cancer, bladder cancer, thyroid cancer, ovarian cancer, cervical cancer, and myelodysplastic syndrome.

Another embodiment relates to a method of treating leukemia, multiple myeloma, or other hematologic malignancies, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating Alzheimer's disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating a Wnt-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating a TGFβ-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating a JAK/STAT-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating an mTOR-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating an AKT-dependent disease, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating or preventing inflammation, inflammatory diseases (e.g., osteoarthritis and rheumatoid arthritis), neurological conditions (e.g., Alzheimer's disease) and neurodegeneration, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating or preventing bone-related diseases and conditions, including osteoporosis and bone formation, or facilitating bone restoration, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating or preventing hypoglycemia, metabolic syndrome and diabetes, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of influencing apoptosis (e.g., increasing the rate of apoptosis in cancerous cells), comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating or preventing aberrant embryonic development, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of inhibiting PIM activity, comprising contacting PIM1, PIM2 or PIM3 with any one of the aforementioned compounds.

Another embodiment relates to a method for treating or preventing a condition associated with aberrant PIM activity, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of modulating Pgp degradation and/or drug efflux activity, comprising contacting a cell with any one of the aforementioned compounds.

Another embodiment relates to a method for treating a malignancy based upon modulation of Pgp, comprising administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.

Another embodiment relates to a method for treating a malignancy comprising co-administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds and a therapeutically effective amount of a known chemotherapy or kinase inhibitor (including but not limited to a PI3K inhibitor, a mTOR inhibitor, or an AKT inhibitor).

DETAILED DESCRIPTION OF THE INVENTION Definitions

The definitions of terms used herein are meant to incorporate the present state-of-the-art definitions recognized for each term in the chemical and pharmaceutical fields. Where appropriate, illustration is provided. The definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.

Where stereochemistry is not specifically indicated, all stereoisomers of the inventive compounds are included within the scope of the invention, as pure compounds as well as mixtures thereof. Unless otherwise indicated, individual enantiomers, diastereomers, geometrical isomers, and combinations and mixtures thereof are all encompassed by the present invention. Polymorphic crystalline forms and solvates are also encompassed within the scope of this invention.

As used herein, the term “isolated” in connection with a compound of the present invention means the compound is not in a cell or organism and the compound is separated from some or all of the components that typically accompany it in nature.

As used herein, the term “pure” in connection with an isolated sample of a compound of the present invention means the isolated sample contains at least 60% by weight of the compound. In certain embodiments, the isolated sample contains at least 70% by weight of the compound. In certain embodiments, the isolated sample contains at least 80% by weight of the compound. In certain embodiments, the isolated sample contains at least 90% by weight of the compound. In certain embodiments, the isolated sample contains at least 95% by weight of the compound. The purity of an isolated sample of a compound of the present invention may be assessed by a number of methods or a combination of them; e.g., thin-layer, preparative, or flash chromatography, mass spectrometry, HPLC, NMR analysis, and the like.

The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term “alkyl” is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, about 6, or about 7 carbons in the ring structure.

Unless the number of carbons is otherwise specified, “lower alkyl” refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.

The term “aralkyl” is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term “aryl” is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics.” The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, —CF₃, —CN, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl”, “heteroaryl”, or “heterocyclic group” are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, piperonyl, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or the like.

The term “optionally substituted” refers to a chemical group, such as alkyl, cycloalkyl aryl, and the like, wherein one or more hydrogen may be replaced with a substituent as described herein, including but not limited to halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, —CF₃, —CN, or the like.

The terms “polycyclyl” or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings”. Rings that are joined through non-adjacent atoms are termed “bridged” rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or the like.

The term “carbocycle” is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

The term “nitro” is art-recognized and refers to —NO₂.

The term “halogen” is art-recognized and refers to —F, —Cl, —Br or —I.

“Halide” designates the corresponding anion of the halogens, and “pseudohalide” has the definition set forth on page 560 of Advanced Inorganic Chemistry by Cotton and Wilkinson.

The term “sulfhydryl” is art-recognized and refers to —SH.

The term “hydroxyl” means —OH.

The term “sulfonyl” is art-recognized and refers to —SO₂ ⁻.

The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or —(CH₂)_(m)—R61. Thus, the term “alkylamine” includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.

The term “acylamino” is art-recognized and refers to a moiety that may be represented by the general formula:

wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or —(CH₂)_(m)—R61, where m and R61 are as defined above.

The term “amido” is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.

The term “alkylthio” refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the “alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl, —S-alkynyl, and —S—(CH₂)_(m)—R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethylthio, and the like.

The term “carboxyl” is art recognized and includes such moieties as may be represented by the general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R61 or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or —(CH₂)_(m)—R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an “ester”. Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a “carboxylic acid”. Where X50 is an oxygen, and R56 is hydrogen, the formula represents a “formate”. In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a “thiolcarbonyl” group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a “thiolester.” Where X50 is a sulfur and R55 is hydrogen, the formula represents a “thiolcarboxylic acid.” Where X50 is a sulfur and R56 is hydrogen, the formula represents a “thiolformate.” On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a “ketone” group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an “aldehyde” group.

The term “carbamoyl” refers to —O(C═O)NRR′, where R and R′ are independently H, aliphatic groups, aryl groups or heteroaryl groups.

The term “oxo” refers to a carbonyl oxygen (═O).

The terms “oxime” and “oxime ether” are art-recognized and refer to moieties that may be represented by the general formula:

wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH₂)_(m)—R61. The moiety is an “oxime” when R is H; and it is an “oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH₂)_(m)—R61.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH₂)_(m)—R61, where m and R61 are described above.

The term “sulfonate” is art recognized and refers to a moiety that may be represented by the general formula:

in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term “sulfate” is art recognized and includes a moiety that may be represented by the general formula:

in which R57 is as defined above.

The term “sulfonamido” is art recognized and includes a moiety that may be represented by the general formula:

in which R50 and R56 are as defined above.

The term “sulfamoyl” is art-recognized and refers to a moiety that may be represented by the general formula:

in which R50 and R51 are as defined above.

The term “sulfonyl” is art-recognized and refers to a moiety that may be represented by the general formula:

in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term “sulfoxido” is art-recognized and refers to a moiety that may be represented by the general formula:

in which R58 is defined above.

The term “phosphoryl” is art-recognized and may in general be represented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:

wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N. When Q50 is S, the phosphoryl moiety is a “phosphorothioate”.

The term “phosphoramidite” is art-recognized and may be represented in the general formulas:

wherein Q51, R50, R51 and R59 are as defined above.

The term “phosphonamidite” is art-recognized and may be represented in the general formulas:

wherein Q51, R50, R51 and R59 are as defined above, and R60 represents a lower alkyl or an aryl.

Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

The definition of each expression, e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled “Standard List of Abbreviations.”

Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.

The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

The phrase “protecting group” as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. Examples of nitrogen protecting groups include an amide (—NRC(═O)R) or a urethane (—NRC(═O)OR), for example, as: a methyl amide (—NHC(═O)CH₃); a benzyloxy amide (—NHC(═O)OCH₂C₆H₅; —NHCbz); as a t-butoxy amide (—NHC(═O)OC(CH₃)₃, —NHBoc); a 2-biphenyl-2-propoxy amide (—NHC(═O)OC(CH₃)₂C₆H₄C₆H₅), as a 9-fluorenylmethoxy amide (—NHFmoc), as a 6-nitroveratryloxy amide (—NHNvoc), as a 2-trimethylsilylethyloxy amide (—NHTeoc), as a 2,2,2-trichloroethyloxy amide (—NHTroc), as an allyloxy amide (—NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (—NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.

The term “pharmaceutically acceptable salt” or “salt” refers to a salt of one or more compounds. Suitable pharmaceutically acceptable salts of compounds include acid addition salts, such as those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and also those formed with organic acids such as maleic acid. For example, acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

Where the compounds carry one or more acidic moieties, pharmaceutically acceptable salts may be formed by treatment of a solution of the compound with a solution of a pharmaceutically acceptable base. Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides and carbonates of alkali metals such as sodium, potassium, and lithium; alkaline earth metal such as calcium and magnesium; and other metals, such as aluminum and zinc. Suitable bases also include ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di alkyl-N-(hydroxy alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

Certain compounds of the invention and their salts may exist in more than one crystalline form (i.e., polymorph); the present invention includes each of the crystal forms and mixtures thereof.

Certain compounds of the invention and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

Certain compounds of the invention may contain one or more chiral centers, and exist in different optically active forms. When compounds of the invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures thereof. The enantiomers may be resolved by methods known to those skilled in the art; for example, enantiomers may be resolved by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example, via enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support; suitable include chiral supports (e.g., silica with a bound chiral ligand) or in the presence of a chiral solvent. Where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step may be used to liberate the desired purified enantiomer. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

When a compound of the invention contains more than one chiral center, it may exist in diastereoisomeric forms. The diastereoisomeric compounds may be separated by methods known to those skilled in the art (for example, chromatography or crystallization) and the individual enantiomers may be separated as described above. The present invention includes the various diastereoisomers of compounds of the invention, and mixtures thereof. Compounds of the invention may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of the invention, and mixtures thereof. For example, any olefins present in the compounds may exist as either the E- or Z-geometric isomers or a mixture thereof unless stated otherwise. Compounds of the invention may exist in zwitterionic form. The present invention includes each zwitterionic form of compounds of the invention, and mixtures thereof.

As used herein the term “pro-drug” refers to an agent, which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. An example, without limitation, of a pro-drug would be a compound of the present invention wherein it is administered as an ester (the “pro-drug”) to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial. Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.

Exemplary pro-drugs release an amine of a compound of the invention wherein the free hydrogen of an amine or alcohol is replaced by —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂, —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂ (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyl-oxymethyl, N—(C₁-C₆)alkoxycarbonylamino-methyl, succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylactyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl wherein said α-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, —P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from detachment of the hydroxyl of the hemiacetal of a carbohydrate).

Other exemplary pro-drugs upon cleavage release a corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., —(CH₂)C(O)OH or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (C₁-C₄)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-((C₄-C₉)alkanoyloxy)ethyl, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl and piperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

The term “subject” as used herein, refers to an animal, typically a mammal or a human, that will be or has been the object of treatment, observation, and/or experiment. When the term is used in conjunction with administration of a compound or drug, then the subject has been the object of treatment, observation, and/or administration of the compound or drug.

The terms “co-administration” and “co-administering” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent at the same time.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a cell culture, tissue system, animal, or human that is being sought by a researcher, veterinarian, clinician, or physician, which includes alleviation of the symptoms of the disease, condition, or disorder being treated.

The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “pharmaceutically acceptable carrier” refers to a medium that is used to prepare a desired dosage form of a compound. A pharmaceutically acceptable carrier can include one or more solvents, diluents, or other liquid vehicles; dispersion or suspension aids; surface active agents; isotonic agents; thickening or emulsifying agents; preservatives; solid binders; lubricants; and the like. Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of Pharmaceutical Excipients, Third Edition, A. H. Kibbe ed. (American Pharmaceutical Assoc. 2000), disclose various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.

Exemplary Compounds

An aspect of the present invention relates to compounds that inhibit casein kinase 1 and/or casein kinase 2 and/or a PIM kinase. For example, an embodiment relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃—R₆;     -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;     -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,         —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R₅ is selected from the group consisting of 1,4-cyclohexanediyl,         1,4-phenylene, 1,4-cycloheptanediyl, 1,4-cyclooctanediyl,         1,5-cyclooctanediyl, 1,4-bicyclo[2.2.1]heptanediyl,         1,4-bicyclo[2.2.2]octanediyl, and 1,5-bicyclo[3.3.1]nonanediyl;     -   R₆ is selected from the group consisting of alkyl, alkylaryl,         aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of         which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of alkyl, alkylaryl, aralkyl (including but not         limited to benzyl), aryl (including but not limited to phenyl),         heteroaryl (including but not limited to pyridyl, imidazolyl,         thiazolyl, furyl, and thionyl), alkoxy (including but not         limited to methoxy), hydroxy, perfluoroalkyl (including but not         limited to trifluoromethyl), trifluoromethoxy, and halide         (including but not limited to fluoride and chloride), wherein         the optional aryl or heteroaryl substituent may be optionally         substituted with alkyl, halide, alkoxy, perfluoroalkyl, or         dioxolanyl;     -   R₇ is selected from the group consisting of H, —C(═NR)R,         —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl,         alkylheteroalkyl, and heteroaryl, any of which is optionally         mono or di-substituted, and the substituents, if present, are         independently selected from the group consisting of alkyl,         alkylaryl, aralkyl, aryl, heteroaryl, alkoxy, hydroxy,         perfluoroalkyl, trifluoromethoxy, and halide, wherein the         optional aryl or heteroaryl substituent may be optionally         substituted with alkyl, halide, alkoxy, perfluoroalkyl, or         dioxolanyl, or     -   two instances of R₇ and the nitrogen to which they are bonded         taken together represent a nitrogen-containing heterocyclyl,         optionally containing one additional heteroatom in the ring,         wherein said additional heteroatom is selected from the group         consisting of —O—, —N(R)—, and —S—;     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl;     -   R is H or (C₁-C₄)alkyl; and     -   n is 1, 2 or 3.

In one embodiment, R′ is H.

In one embodiment, R′ is methyl.

In one embodiment, R′ is (C₂-C₄)alkyl.

In one embodiment, R′ is benzyl.

In one embodiment, R₂ is H.

In one embodiment, R₂ is —CH₂OP(═O)(OH)₂.

In one embodiment, R₅ is 1,4-cyclohexanediyl.

In one embodiment, R₅ is 1,4-phenylene.

In one embodiment, R₆ is selected from the group consisting of alkyl, aryl, and heteroaryl.

In one embodiment, R₆ is selected from the group consisting of phenyl, biphenyl, pyridyl, pyrimidyl, naphthyl, quinolinyl, furanyl, and thienyl.

In one embodiment, R₆ is phenyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is phenyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyridyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyridyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyrimidyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyrimidyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is naphthyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is naphthyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is naphthyl; and the substituent is fluoride.

In one embodiment, R₆ is quinolinyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is quinolinyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is quinolinyl; and the substituent is methyl.

In one embodiment, R₈ is H.

One aspect of the invention is a compound of formula 2 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃—R₄;     -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;     -   R₁ is selected from the group consisting of 1,4-cyclohexanediyl         and 1,4-phenylene;     -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,         —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R₄ is selected from the group consisting of aryl and heteroaryl,         either of which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of halide, alkyl, perfluoroalkyl, aryl,         heteroaryl, and heterocyclyl; wherein the optional aryl or         heteroaryl substituent is itself optionally substituted with         perfluoroalkyl or dioxolane;     -   R₇ is selected from the group consisting of H, —C(═NR)R,         —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl,         alkylheteroalkyl, and heteroaryl, any of which is optionally         mono or di-substituted, and the substituents, if present, are         independently selected from the group consisting of alkyl,         alkylaryl, aralkyl (including but not limited to benzyl), aryl         (including but not limited to phenyl), heteroaryl (including but         not limited to pyridyl, imidazolyl, thiazolyl, furyl, and         thionyl), alkoxy (including but not limited to methoxy),         hydroxy, perfluoroalkyl (including but not limited to         trifluoromethyl), trifluoromethoxy, and halide (including but         not limited to fluoride and chloride), wherein the optional aryl         or heteroaryl substituent may be optionally substituted with         alkyl, halide, alkoxy, perfluoroalkyl, or dioxolanyl, or     -   two instances of R₇ and the nitrogen to which they are bonded         taken together represent a nitrogen-containing heterocyclyl,         optionally containing one additional heteroatom in the ring,         wherein said additional heteroatom is selected from the group         consisting of —O—, —N(R)—, and —S—;     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl;     -   R is H or (C₁-C₄)alkyl; and     -   n is 1, 2 or 3.

In one embodiment, R′ is H.

In one embodiment, R′ is methyl.

In one embodiment, R′ is (C₂-C₄)alkyl.

In one embodiment, R′ is benzyl.

In one embodiment, R₁ is 1,4-cyclohexanediyl.

In one embodiment, R₁ is 1,4-phenylene.

In one embodiment, R₄ is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, furanyl, and thienyl.

In one embodiment, R₄ is phenyl, and the substituents are independently selected from the group consisting of fluoride, furyl, and thienyl.

In one embodiment, R₄ is pyridyl, and the substituents are independently selected from the group consisting of halide, aryl, heteroaryl, and heterocyclyl; wherein the aryl and heteroaryl are optionally substituted with perfluoroalkyl or dioxolane.

In one embodiment, R₄ is pyridyl, and the substituents are independently selected from the group consisting fluoride, furyl, thienyl, trifluormethylphenyl, trifluoromethylthienyl, and 1,3 benzodioxozole.

In one embodiment, R₄ is naphthyl, and the substituent is fluoride.

In one embodiment, R₄ is quinolinyl, and the substituent is methyl.

In one embodiment, the invention relates to any one of the aforementioned compounds, wherein X is —N(R₇)₂, and —N(R₇)₂ represents

In one embodiment, the invention relates to any one of the aforementioned compounds, wherein R₃ is selected from the group consisting of —CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH₂CH₂CH₂—, and —C(═NH)—.

Another embodiment relates to a compound of formula 3 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,         —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(m);     -   R is H or (C₁-C₄)alkyl;     -   n is 1, 2 or 3;     -   R₆ is selected from the group consisting of alkyl, alkylaryl,         aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of         which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of alkyl, alkylaryl, aralkyl (including but not         limited to benzyl), aryl (including but not limited to phenyl),         heteroaryl (including but not limited to pyridyl, imidazolyl,         thiazolyl, furyl, and thionyl), alkoxy (including but not         limited to methoxy), hydroxy, perfluoroalkyl (including but not         limited to trifluoromethyl), trifluoromethoxy, and halide         (including but not limited to fluoride and chloride), wherein         the optional aryl or heteroaryl substituent may be optionally         substituted with alkyl, halide, alkoxy, perfluoroalkyl, or         dioxolanyl; and     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

In one embodiment, R₂ is H.

In one embodiment, R₂ is —CH₂OP(═O)(OH)₂.

In one embodiment, R₃ is —CH₂—.

In one embodiment, R₆ is selected from the group consisting of alkyl, aryl, and heteroaryl.

In one embodiment, R₆ is selected from the group consisting of phenyl, biphenyl, pyridyl, pyrimidyl, naphthyl, quinolinyl, furanyl, and thienyl.

In one embodiment, R₆ is phenyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is phenyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyridyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyridyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyrimidyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyrimidyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is naphthyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is naphthyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is naphthyl; and the substituent is fluoride.

In one embodiment, R₆ is quinolinyl; the substituents are independently selected from the group consisting of alkyl, aryl, heteroaryl, alkoxy, perfluoroalkyl, halide; and the aryl or heteroaryl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is quinolinyl; the substituents are independently selected from the group consisting of phenyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl, furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl, furyl, or thienyl substituent is substituted with a substituent selected from the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is quinolinyl; and the substituent is methyl.

In one embodiment, R₈ is H.

Another embodiment relates to a compound of formula 4 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R is H or (C₁-C₄)alkyl;     -   n is 1, 2 or 3; and     -   R₄ is selected from the group consisting of aryl and heteroaryl,         either of which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of halide, alkyl, perfluoroalkyl, aryl,         heteroaryl, and heterocyclyl; wherein the optional aryl or         heteroaryl substituent is itself optionally substituted with         perfluoroalkyl or dioxolane.

In one embodiment, R₄ is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, furanyl, and thienyl.

In one embodiment, R₄ is phenyl, and the substituents are independently selected from the group consisting of fluoride, furyl, and thienyl.

In one embodiment, R₄ is pyridyl, and the substituents are independently selected from the group consisting of halide, aryl, heteroaryl, and heterocyclyl; wherein the aryl and heteroaryl are optionally substituted with perfluoroalkyl or dioxolane.

In one embodiment, R₄ is pyridyl, and the substituents are independently selected from the group consisting fluoride, furyl, thienyl, trifluormethylphenyl, trifluoromethylthienyl, and 1,3 benzodioxozole.

In one embodiment, R₄ is naphthyl, and the substituent is fluoride.

In one embodiment, R₄ is quinolinyl, and the substituent is methyl.

In one embodiment, R₃ is selected from the group consisting of —CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH₂CH₂CH₂—, and —C(═NH)—.

Another embodiment relates to a compound of formula 5 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;     -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,         —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;     -   R is H or (C₁-C₄)alkyl;     -   n is 1, 2 or 3;     -   R₆ is selected from the group consisting of alkyl, alkylaryl,         aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of         which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of alkyl, alkylaryl, aralkyl (including but not         limited to benzyl), aryl (including but not limited to phenyl),         heteroaryl (including but not limited to pyridyl, imidazolyl,         thiazolyl, furyl, and thionyl), alkoxy (including but not         limited to methoxy), hydroxy, perfluoroalkyl (including but not         limited to trifluoromethyl), trifluoromethoxy, and halide         (including but not limited to fluoride and chloride), wherein         the optional aryl or heteroaryl substituent may be optionally         substituted with alkyl, halide, alkoxy, perfluoroalkyl, or         dioxolanyl; and     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

In one embodiment, R′ is H.

In one embodiment, R′ is methyl.

In one embodiment, R′ is (C₂-C₄)alkyl.

In one embodiment, R′ is benzyl.

In one embodiment, R₂ is H.

In one embodiment, R₂ is —CH₂OP(═O)(OH)₂.

Another embodiment relates to a compound of formula 6 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;     -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,         —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;     -   R₃ is —C(═NR)— or —(C(R)₂)_(m)—;     -   R is H or (C₁-C₄)alkyl;     -   n is 1, 2 or 3;     -   R₆ is selected from the group consisting of alkyl, alkylaryl,         aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of         which is optionally mono or di-substituted, and the         substituents, if present, are independently selected from the         group consisting of alkyl, alkylaryl, aralkyl (including but not         limited to benzyl), aryl (including but not limited to phenyl),         heteroaryl (including but not limited to pyridyl, imidazolyl,         thiazolyl, furyl, and thionyl), alkoxy (including but not         limited to methoxy), hydroxy, perfluoroalkyl (including but not         limited to trifluoromethyl), trifluoromethoxy, and halide         (including but not limited to fluoride and chloride), wherein         the optional aryl or heteroaryl substituent may be optionally         substituted with alkyl, halide, alkoxy, perfluoroalkyl, or         dioxolanyl; and     -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

In one embodiment, R′ is H.

In one embodiment, R′ is methyl.

In one embodiment, R′ is (C₂-C₄)alkyl.

In one embodiment, R′ is benzyl.

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

In one embodiment, the compound is selected from the group consisting of:

Any one of the aforementioned compounds may exist as the E-geometric isomer, the Z-geometric isomer, or mixtures thereof. For example, in one embodiment,

in the aforementioned structures represents the E-isomer of the particular compound. In another embodiment,

represents the Z-isomer of the particular compound. In yet another embodiment,

represents a mixture of E and Z isomers of the particular compound.

In one embodiment, any one of the aforementioned compounds is an inhibitor of CK1, CK1γ1, CK1γ2, or CK1γ3.

In one embodiment, any one of the aforementioned compounds is an inhibitor of CK2.

In one embodiment, any one of the aforementioned compounds is an inhibitor of the Wnt pathway.

In one embodiment, any one of the aforementioned compounds is an inhibitor of the JAK/STAT pathway.

In one embodiment, any one of the aforementioned compounds is an inhibitor of the mTOR pathway.

In one embodiment, any one of the aforementioned compounds is an inhibitor of the AKT pathway.

In one embodiment, any one of the aforementioned compounds is a mediator of Pgp degradation and/or drug efflux.

In one embodiment, any one of the aforementioned compounds is an inhibitor of the TGFβ pathway.

In some embodiments, the compound has an IC₅₀ of less than about 5000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC₅₀ of less than about 1000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC₅₀ of less than about 500 nM for CK1, CK1γ1, CK1γ2, or CK1γ3.

In one embodiment, any one of the aforementioned compounds is an inhibitor of CK2.

In one embodiment, the compound has an IC₅₀ of less than about 5000 nM for CK2.

In one embodiment, the compound has an IC₅₀ of less than about 1000 nM for CK2.

In one embodiment, the compound has an IC₅₀ of less than about 500 nM for CK2.

In one embodiment, any one of the aforementioned compounds is an inhibitor of PIM1, PIM2, or PIM3.

In one embodiment, the compound has an IC₅₀ of less than about 5000 nM for PIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC₅₀ of less than about 1000 nM for PIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC₅₀ of less than about 500 nM for PIM1, PIM2 or PIM3.

In addition, it may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term “chemically protected form,” as used herein, pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions (i.e., they have been modified with a protecting group).

By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

For example, a hydroxy group may be protected as an ether (—OR) or an ester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃,—OAc).

For example, an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (C(═O)) is converted to a diether (C(OR)₂), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide (—NRC(═O)R) or a urethane (—NRC(═O)OR), for example, as: a methyl amide (—NHC(═O)CH₃); a benzyloxy amide (—NHC(═O)OCH₂C₆H₅; —NHCbz); as a t-butoxy amide (—NHC(═O)OC(CH₃)₃, —NHBoc); a 2-biphenyl-2-propoxy amide (—NHC(═O)OC(CH₃)₂C₆H₄C₆H₅), as a 9-fluorenylmethoxy amide (—NHFmoc), as a 6-nitroveratryloxy amide (—NHNvoc), as a 2-trimethylsilylethyloxy amide (—NHTeoc), as a 2,2,2-trichloroethyloxy amide (—NHTroc), as an allyloxy amide (—NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (—NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical.

For example, a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.

For example, a thiol group may be protected as a thioether (—SR), for example, as: a benzyl thioether; or an acetamidomethyl ether (—SCH₂NHC(═O)CH₃).

Exemplary Pharmaceutical Compositions

One or more compounds of this invention can be administered to a mammal by themselves or in pharmaceutical compositions where they are mixed with suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. For example, one aspect of the invention relates to pharmaceutical composition comprising a therapeutically effective dose of a compound of formula 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt, solvate, enantiomer or stereoisomer thereof; and a pharmaceutically acceptable diluent or carrier.

Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition.

Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.

Alternatively, one may administer a compound in a local rather than a systemic manner, for example, via injection of the compound directly into an oedematous site, often in a depot or sustained release formulation.

Furthermore, one may administer a compound in a targeted drug delivery system, for example, in a liposome coated with endothelial-cell-specific antibody.

The pharmaceutical compositions of the present invention may be manufactured, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants are used in the formulation appropriate to the barrier to be permeated. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable vehicle, e.g., sterile pyrogen-free water.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt).

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also may be employed. Additionally, the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

The pharmaceutical compositions may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers, such as polyethylene glycols.

Exemplary Methods of Treatment

Provided herein are methods of modulating the activity of CK1 and subtypes thereof, CK2, the Wnt pathway, and/or the TGFβ pathway. Also provided herein are methods of treating or preventing conditions and diseases the course of which can be influenced by modulating the activity of CK1 (e.g., CK1γ), CK2, the Wnt pathway, and/or the TGFβ pathway. Such methods typically comprise administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.

Also provided herein are methods of modulating the activity of PIM, such as PIM 1, PIM 2 or PIM 3, the JAK/STAT pathway, the AKT pathway, and/or the mTOR pathway, and/or Pgp. Also provided herein are methods of treating or preventing conditions and diseases, the course of which can be influenced by modulating the activity of the PIMs, the JAK/STAT pathway, the AKT pathway, and/or the mTOR pathway, and/or Pgp. Such methods typically comprise administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.

Various diseases, such as cancers, inflammation, and inflammatory diseases (e.g., osteoarthritis and rheumatoid arthritis), and neurological conditions (e g, Alzheimer's disease) and neurodegeneration can be treated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Bone-related diseases and conditions, including osteoporosis and bone formation, also can be treated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Bone restoration can be facilitated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Additional conditions that can be treated by administration of modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway include hypoglycemia, metabolic syndrome and diabetes. Modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway are also useful for influencing apoptosis (e.g., increasing the rate of apoptosis in cancerous cells). Modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway are also useful in treatment or prevention of aberrant embryonic development.

Based at least on the fact that increased CK1γ has been found to be associated with certain cancers, a method for treating cancer in a subject comprises administering to the subject in need thereof a therapeutically effective amount of a compound that inhibits CK1γ. PIM1, PIM2, PIM3, the JAK/STAT pathway, the AKT pathway, and/or the mTOR pathway have also been found to be associated with certain cancers. Therefore, provided herein is a method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound that inhibits PIM1 and/or PIM2 and/or PIM3.

PIM1, PIM2, and PIM3 have also been associated with protecting Pgp from degradation, which can regulate drug efflux and drug resistance. Therefore, provided herein is a method for treating malignancies comprising administering to a subject in need thereof a therapeutically effective amount of a compound that inhibits PIM1 and/or PIM2 and/or PIM3 in conjunction with another drug, compound or material to abrogate resistance to the drug, compound or material.

The compounds described herein can be used for modulating cell proliferation, generally. Accordingly, diseases that may be treated include hyperproliferative diseases, such as benign cell growth and malignant cell growth.

Exemplary cancers that may be treated include leukemias, e.g., acute lymphoid leukemia and myeloid leukemia, and carcinomas, such as colorectal carcinoma and hepatocarcinoma. Other cancers include Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Adrenocortical Carcinoma Adrenocortical Carcinoma; AIDS-Related Cancers; AIDS-Related Lymphoma; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Basal Cell Carcinoma, see Skin Cancer (non-Melanoma); Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bone Cancer, osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma; Brain Tumor; Brain Tumor, Brain Stem Glioma; Brain Tumor, Cerebellar Astrocytoma; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma; Brain Tumor, Ependymoma; Brain Tumor, Medulloblastoma; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors; Brain Tumor, Visual Pathway and Hypothalamic Glioma; Brain Tumor; Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer; Breast Cancer, Male; Bronchial Adenomas/Carcinoids; Burkitt's Lymphoma; Carcinoid Tumor; Carcinoid Tumor, Gastrointestinal; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma; Cerebral Astrocytoma/Malignant Glioma; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Colon Cancer; Colorectal Cancer; Cutaneous T-Cell Lymphoma, see Mycosis Fungoides and Sezary Syndrome; Endometrial Cancer; Ependymoma; Esophageal Cancer; Ewing's Family of Tumors; Extracranial Germ Cell Tumor; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma; Glioma, Childhood Brain Stem; Glioma, Childhood Cerebral Astrocytoma; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hematologic (Blood) Cancer, Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney (Renal Cell) Cancer; Kidney Cancer; Laryngeal Cancer; Leukemia, Acute Lymphoblastic; Leukemia, Acute Lymphoblastic; Leukemia, Acute Myeloid; Leukemia, Acute Myeloid; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoma, AIDS-Related; Lymphoma, Burkitt's; Lymphoma, Cutaneous T-Cell, see Mycosis Fungoides and Sezary Syndrome; Lymphoma, Hodgkin's; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Malignant Fibrous Histiocytoma of Bone/Osteosarcoma; Medulloblastoma; Melanoma; Melanoma, Intraocular (Eye); Merkel Cell Carcinoma; Mesothelioma, Adult Malignant; Mesothelioma; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Adult Acute; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Neuroblastoma; Non-Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer; Oral Cavity Cancer, Lip and; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma, Soft Tissue; Sarcoma, Uterine; Sezary Syndrome; Skin Cancer (non-Melanoma); Skin Cancer; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; Squamous Cell Carcinoma, see Skin Cancer (non-Melanoma); Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma, Cutaneous, see Mycosis Fungoides and Sezary Syndrome; Testicular Cancer; Thymoma; Thymoma and Thymic Carcinoma; Thyroid Cancer; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Carcinoma of; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Cancer, Endometrial; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma; Vulvar Cancer; Waldenstrom's Macroglobulinemia; Wilms' Tumor; and Women's Cancers.

Neurologic diseases that may be treated include epilepsy, schizophrenia, bipolar disorder or other psychological and/or psychiatric disorders, neuropathies, skeletal muscle atrophy, and neurodegenerative diseases, e.g., a neurodegenerative disease. Exemplary neurodegenerative diseases include: Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), and Parkinson's disease. Another class of neurodegenerative diseases includes diseases caused at least in part by aggregation of poly-glutamine. Diseases of this class include: Huntington's Diseases, Spinalbulbar Muscular Atrophy (SBMA or Kennedy's Disease), Dentatorubropallidoluysian Atrophy (DRPLA), Spinocerebellar Ataxia 1 (SCA1), Spinocerebellar Ataxia 2 (SCA2), Machado-Joseph Disease (MJD; SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCAT), and Spinocerebellar Ataxia 12 (SCA12).

Any other disease in which the Wnt pathway, TGFβ pathway, JAK/STAT pathway, the mTOR pathway, the AKT pathway, Pgp modulation, CK1, CK1γ, CK2, or PIMs plays a role may be treatable or preventable using compounds and methods described herein.

Exemplary Dosage

As used herein, a “therapeutically effective amount” or “therapeutically effective dose” is an amount of a compound of the invention or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition. A therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount may be determined by methods known to those of skill in the art.

A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED₅₀ (effective dose for 50% maximal response). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED₅₀. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. In the treatment of crises, the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.

Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the CK1, CK1γ, CK2, Pim1-3, Wnt pathway, TGFβ pathway, JAK/STAT pathway, AKT pathway, mTOR pathway, or Pgp modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using the MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for about 10-90% of the time, between about 30-90%, or between about 50-90% until the desired amelioration of symptoms is achieved. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

Exemplary Kits

The compounds and compositions of the invention (e.g., compounds and compositions of formula 1, 2, 3, 4, 5, or 6) may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition. Instructions for use may also be provided.

EXEMPLIFICATION

The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. The geometric isomers depicted below are believed to be correct, but final structural assignment can be made via 2-D NMR experiments. Although the exemplary compounds described below are believed to be the Z-geometric isomers, the E-geometric isomers and mixtures of the E- and Z-isomers are also contemplated by the present disclosure.

Example 1

(E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1)

1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and 1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110° C. for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 130 g of the crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 143 g theoretical, 91%). LC-MS m/z 283 (M+1). Reference: WO 2006/0097341A1, pg 67.

Example 2

Sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2)

A solution of thiourea (64.7 g, 850 mmol, 1.13 equiv.), sodium methanolate (95%, 40.5 g, 751 mmol, 1.0 equiv.) in methanol (500 mL, 1.5 M) was stirred at room temperature for 30 minutes. A solution of (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 751 mmol) in methanol (200 mL) was added and the reaction stirred at room temperature for 2 h. The crude sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) was used directly in the next step without further purification. LC-MS m/z 209 (M+1). Reference: WO 2006/0097341A1, pg 67.

Example 3

4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3)

Iodomethane (128 g, 902 mmol, 1.20 equiv.) was added carefully to the crude solution of sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) (156 g, 751 mmol) in methanol (700 mL, 1.1 M) while maintaining the reaction temperature below 28° C. using an ice-water bath for cooling. The resulting mixture was stirred at room temperature for 16 h. After removal of the solvent under reduced pressure, the residue was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was concentrated under reduced pressure and the crude residue purified by passing through a short silica gel pad and washing with diethyl ether (200 mL) to afford 4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) as a brown oil (53.7 g, 150 g theoretical, 35.7%). LC-MS m/z 201 (M+1). Reference: WO 2006/0097341A1, pg 67.

Example 4

2-(methylthio)pyrimidine-4-carbaldehyde (4)

4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) (53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL, 268 mmol, 1.0 equiv.) and stirred at 60° C. for 3 hours. The reaction mixture was then cooled to room temperature and neutralized by the slow addition of solid sodium bicarbonate. The crude mixture was extracted with diethyl ether (3×150 mL) and the combined organic layer was concentrated under reduced pressure to afford 2-(methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g, 41.5 g theoretical, 34%). LC-MS m/z 155 (M+1). Reference: WO 2006/009734 A1, pg 67.

Example 5

(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5)

A 40 mL round-bottomed vial was charged with 2-(methylthio)pyrimidine-4-carbaldehyde (4) (771 mg, 5 mmol), thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv.), and piperidine (400 μL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80° C. and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol (1×20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254 (M+1).

Example 6

(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (6)

A mixture of (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) (3.5 g, 13.82 mmol) in THF (100 mL, 0.13 M) was treated with a solution of oxone (25.8 g, 41.5 mmol, 3.0 equiv.) in water (175 mL). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was filtered and washed with water (20 mL) and diethyl ether (20 mL) to afford (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (6) as a solid (2.48 g, 3.94 g theoretical, 63%). LC-MS m/z 286 (M+1).

Example 7

General Displacement Procedure

2-dram round bottomed vials were charged with (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (25 mg, 0.0877 mmol) prepared according to the general procedure, DMSO (1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.296 mmol, 3.2 equiv.), and the appropriate amine (0.0877 mmol, 1.0 equiv.). The reaction mixture was heated to 110° C. and shaken for 24 h. The solvent was removed under reduced pressure (genvac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac (HT-4)).

Example 8 Displacement/De-Protection of Mono-Boc Diamines

General De-Protection Procedure:

The crude protected amine was prepared using the General Displacement Procedure and was then treated with 2 mL DCE and 500 μL of TFA and shaken for 24 h. The solvent was removed under reduced pressure (Genevac HT-4) and the crude residues were purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as a modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4).

Example 9

General Reductive Amination Procedure 1 (Aldehydes)

A 2-dram round bottomed vial was charged with the crude amine/TFA salt prepared using the general displacement procedure followed by the general TFA de-protection procedure (0.115 mmol), DCE (2 mL), DIPEA (6 eq. 0.690 mmol), DMF (1 mL), the aldehyde (1 equiv., 0.115 mmol), and the reaction mixture was shaken for 1 h at RT. The reaction mixture was then treated with NaBH(OAc)₃ (2.5 equiv., 0.230 mmol) and the reaction was shaken 16 h at RT. The reaction mixture was then diluted with DCE (2 mL) and NaHCO₃ (2 mL). The aqueous layer was back extracted with DCE (2×2 mL) and the combined organic layer was concentrated under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and triflouroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to afford the pure products as the TFA salt.

Example 10

General Reductive Amination Procedure 2 (Ketones)

A 2-dram round bottomed vial was charged with the crude amine/TFA salt prepared using the general displacement procedure followed by the general TFA de-protection procedure (0.115 mmol), DCE (2 mL), DIPEA (6 eq. 0.690 mmol), DMF (1 mL), the ketone (1 equiv., 0.115 mmol), and the reaction mixture was shaken for 1 h at RT. The reaction mixture was then treated with NaBH(OAc)₃ (2.5 equiv., 0.230 mmol) and the reaction was shaken 16 h at RT. The reaction mixture was then diluted with DCE (2 mL) and NaHCO₃ (2 mL). The aqueous layer was back extracted with DCE (2×2 mL) and the combined organic layer was concentrated under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and triflouroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to afford the pure products as the TFA salt.

Example 11

General Procedure for the Preparation of Sulfonamides/Amides

A 2-dram round-bottomed vial was charged with the appropriate sulfonyl chloride or acid chloride (0.072 mmol, 1 equiv.) in 0.5 mL of DMF, and then treated carefully with a solution of (Z)-5-((2-(((1r,4r)-4-aminocyclohexyeamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione, prepared using the general displacement procedure followed by the general de-protection procedure where appropriate, (0.072 mmol, 1 equiv.), DIPEA (0.296 mmol, 4 equiv.), and 1 mL of DMF. The reaction mixture was then shaken at room temperature overnight. The reaction mixture was partitioned between 2 mL DCE and 1 mL sat. NaHCO₃ and the aqueous layer was extracted with DCE (2×2 mL). The combined organic layer was the concentrated under reduced pressure (Genevac HT-4) and the crude residue was purified using reverse phase HPLC (MS-triggered fraction collection) with an acetonitrile/water or methanol/water gradient and trifluoroacetic acid as the modifier. The pure fractions were then concentrated under reduced pressure (Genevac HT-4) to afford the sulfonamide and amide analogs.

Example 12

(Z)-5-((2-(((1-((6-(thiophen-3-yl)pyridin-2-yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(thiophen-3-yl)picolinaldehyde (38.8 g, 46.8 mg theoretical, 83%). LC-MS m/z 493 (M+1).

Example 13

(Z)-5-((2-(((1-((6-methylpyridin-2-yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-methylpicolinaldehyde (40.3 mg, 51.2 mg theoretical, 79%). LC-MS m/z 425 (M+1).

Example 14

(Z)-5-((2-(((1-((6-fluoropyridin-2-yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-fluoropicolinaldehyde (16.2 mg, 40.7 mg theoretical, 39.8%). LC-MS m/z 429 (M+1).

Example 15

(Z)-5-((2-(((1-(pyridin-3-ylmethyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and nicotinaldehyde (38.6 mg, 49.8 mg theoretical, 77%). LC-MS m/z 411 (M+1).

Example 16

(Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(thiophen-3-yl)picolinaldehyde (4.5 mg, 35.5 mg theoretical, 12.7%). LC-MS m/z 493 (M+1).

Example 17

(Z)-5-((2-((trans-4-(((2-methylquinolin-4-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-methylquinoline-4-carbaldehyde (2.5 mg, 34.2 mg theoretical, 7%). LC-MS m/z 475 (M+1).

Example 18

(Z)-5-((2-((trans-4-((1-(6-(thiophen-3-yl)pyridin-2-yl)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 2 and 1-(6-(thiophen-3-yl)pyridin-2-yl)ethanone (3.4 mg, 36.5 mg theoretical, 9%). LC-MS m/z 507 (M+1).

Example 19

(Z)-5-((2-((cis-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(thiophen-3-yl)picolinaldehyde (4.5 mg, 35.5 mg theoretical, 12.7%). LC-MS m/z 493 (M+1).

Example 20

(Z)-5-((2-((trans-4-(((6-(thiophen-2-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(thiophen-2-yl)picolinaldehyde (16.9 mg, 35.5 mg theoretical, 47%). LC-MS m/z 493 (M+1).

Example 21

(Z)-5-((2-((trans-4-(((2-(furan-3-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(furan-3-yl)nicotinaldehyde (4.3 mg, 34.3 mg theoretical, 12.5%). LC-MS m/z 477 (M+1).

Example 22

(Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(thiophen-3-yl)picolinaldehyde (4.5 mg, 35.5 mg theoretical, 12.7%). LC-MS m/z 493 (M+1).

Example 23

(Z)-5-((2-((trans-4-(((2-(thiophen-3-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(thiophen-3-yl)nicotinaldehyde (6.8 mg, 35.5 mg theoretical, 19.2%). LC-MS m/z 473 (M+1).

Example 24

(Z)-5-((2-((trans-4-(((2-(furan-2-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(furan-2-yl)nicotinaldehyde (5.6 mg, 34.3 mg theoretical, 16.3%). LC-MS m/z 477 (M+1).

Example 25

(Z)-5-((2-((trans-4-(((6-(furan-2-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(furan-2-yl)picolinaldehyde (6.5 mg, 34.3 mg theoretical, 18.9%). LC-MS m/z 477 (M+1).

Example 26

(Z)-5-((2-((trans-4-((4-fluoro-2-(furan-2-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-fluoro-2-(furan-2-yl)benzaldehyde (1 mg, 35.5 mg theoretical, 2.8%). LC-MS m/z 494 (M+1).

Example 27

(Z)-5-((2-((trans-4-(((6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(2-(trifluoromethyl)phenyl)picolinaldehyde (6.6 mg, 39.9 mg theoretical, 16.5%). LC-MS m/z 555 (M+1).

Example 28

(Z)-5-((2-((trans-4-((3-(thiophen-2-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 3-(thiophen-2-yl)benzaldehyde (8.6 mg, 35.4 mg theoretical, 24.3%). LC-MS m/z 492 (M+1).

Example 29

(Z)-5-((2-((trans-4-(((6-fluoronaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-fluoro-2-naphthaldehyde (6.8 mg, 34.4 mg theoretical, 19.8%). LC-MS m/z 478 (M+1).

Example 30

(Z)-5-((2-((trans-4-(phenethylamino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-phenylacetaldehyde (4.2 mg, 30.5 mg theoretical, 13.8%). LC-MS m/z 424 (M+1).

Example 31

(Z)-5-((2-((cis-4-(phenethylamino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-phenylacetaldehyde (9.5 mg, 30.5 mg theoretical, 31%). LC-MS m/z 424 (M+1).

Example 32

(Z)-5-((2-((cis-4-((1-(6-(thiophen-3-yl)pyridin-2-yl)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 2 and 1-(6-(thiophen-3-yl)pyridin-2-yl)ethanone (2.3 mg, 36.5 mg theoretical, 6%). LC-MS m/z 507 (M+1).

Example 33

(Z)-5-((2-((cis-4-(((2-methylquinolin-4-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-methylquinoline-4-carbaldehyde (3.1 mg, 34.2 mg theoretical, 9%). LC-MS m/z 475 (M+1).

Example 34

(Z)-5-((2-((trans-4-(((6-(benzo[d][1,3]dioxol-5-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(benzo[d][1,3]dioxol-5-yl)picolinaldehyde (11.3 mg, 38.2 mg theoretical, 30%). LC-MS m/z 531 (M+1).

Example 35

(Z)-5-((2-((trans-4-(((2-(5-(trifluoromethyl)thiophen-2-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(5-(trifluoromethyl)thiophen-2-yl)nicotinaldehyde (3.4 mg, 40.4 mg theoretical, 7%). LC-MS m/z 561 (M+1).

Example 36

(Z)-5-((2-((trans-4-((2-(pyridin-2-yl)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(pyridin-2-yl)acetaldehyde (2.5 mg, 44.6 mg theoretical, 1%). LC-MS m/z 425 (M+1).

Example 37

(Z)-5-((2-((trans-4-(((3-(trifluoromethyl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 3-(trifluoromethyl)picolinaldehyde (31.8 mg, 62.7 mg theoretical, 50.7%). LC-MS m/z 479.5 (M+1).

Example 38

(Z)-5-((2-((trans-4-(((6-fluoroquinolin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-fluoroquinoline-2-carbaldehyde (4.3 mg, 34.5 mg theoretical, 12.5%). LC-MS m/z 479.5 (M+1).

Example 39

(Z)-5-((2-((trans-4-(((6-(furan-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(furan-3-yl)picolinaldehyde (6.1 mg, 35.4 mg theoretical, 17%). LC-MS m/z 492 (M+1).

Example 40

(Z)-5-((2-((trans-4-(((1-bromonaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 1-bromo-2-naphthaldehyde (1.1 mg, 38.8 mg theoretical, 2.8%). LC-MS m/z 539.5 (M+1).

Example 41

(Z)-5-((2-((trans-4-((quinolin-5-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and quinoline-5-carbaldehyde (1.1 mg, 33.2 mg theoretical, 3.3%). LC-MS m/z 461.5 (M+1).

Example 42

(Z)-5-((2-((trans-4-((naphthalen-1-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 1-naphthaldehyde (4 mg, 33.1 mg theoretical, 12.1%). LC-MS m/z 460.5 (M+1).

Example 43

(Z)-5-((2-((trans-4-(((6-hydroxynaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-hydroxy-2-naphthaldehyde (3.3 mg, 34.2 mg theoretical, 9.6%). LC-MS m/z 476.5 (M+1).

Example 44

(Z)-5-((2-((trans-4-4(((2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde (8.4 mg, 39.9 mg theoretical, 21%). LC-MS m/z 554.5 (M+1).

Example 45

(Z)-5-((2-((trans-4-(((6-methoxynaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-methoxy-2-naphthaldehyde (3.3 mg, 35.3 mg theoretical, 9.4%). LC-MS m/z 490.5 (M+1).

Example 46

(Z)-5-((2-((trans-4-(((4′-fluoro-[1,1′-biphenyl]-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4′-fluoro-[1,1′-biphenyl]-2-carbaldehyde (8 mg, 36.3 mg theoretical, 22.1%). LC-MS m/z 504.5 (M+1).

Example 47

(Z)-5-((2-((trans-4-((4-fluoro-2-(pyridin-3-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-fluoro-2-(pyridin-3-yl)benzaldehyde (11.3 mg, 36.3 mg theoretical, 31.1%). LC-MS m/z 505.5 (M+1).

Example 48

(Z)-5-((2-((trans-4-(((2-(benzofuran-2-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(benzofuran-2-yl)nicotinaldehyde (7.9 mg, 37.9 mg theoretical, 20.8%). LC-MS m/z 527.6 (M+1).

Example 49

(Z)-5-((2-((trans-4-(((2-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(3-(trifluoromethoxy)phenyl)nicotinaldehyde (2.6 mg, 41.1 mg theoretical, 6.3%). LC-MS m/z 571.5 (M+1).

Example 50

(Z)-5-((2-((trans-4-(((2-(2-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(2-(trifluoromethyl)phenyl)nicotinaldehyde (2 mg, 39.9 mg theoretical, 5%). LC-MS m/z 555.5 (M+1).

Example 51

(Z)-5-((2-((trans-4-4(((4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbaldehyde (22.7 mg, 39.9 mg theoretical, 50%). LC-MS m/z 554.6 (M+1).

Example 52

(Z)-5-((2-((trans-4-((2-(pyridin-4-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(pyridin-4-yl)benzaldehyde (10.2 mg, 35 mg theoretical, 29.1%). LC-MS m/z 487.5 (M+1).

Example 53

(Z)-5-((2-((trans-4-(((2-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(3-(trifluoromethyl)phenyl)nicotinaldehyde (6.4 mg, 39.9 mg theoretical, 16%). LC-MS m/z 555.5 (M+1).

Example 54

(Z)-5-((2-((trans-4-(((2-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(4-(trifluoromethyl)phenyl)nicotinaldehyde (5.9 mg, 39.9 mg theoretical, 14.8%). LC-MS m/z 555.5 (M+1).

Example 55

(Z)-5-((2-((trans-4-(((5-fluoro-[1,1′-biphenyl]-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 5-fluoro-[1,1′-biphenyl]-2-carbaldehyde (6.9 mg, 36.3 mg theoretical, 19%). LC-MS m/z 504.6 (M+1).

Example 56

(Z)-5-((2-((trans-4-((2-(furan-2-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(furan-2-yl)benzaldehyde (5.4 mg, 34.2 mg theoretical, 15.8%). LC-MS m/z 476.5 (M+1).

Example 57

(Z)-5-((2-((trans-4-((2-(furan-3-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(furan-3-yl)benzaldehyde (7.2 mg, 34.2 mg theoretical, 21%). LC-MS m/z 476.5 (M+1).

Example 58

(Z)-5-((2-((trans-4-(((4-fluoronaphthalen-1-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-fluoro-1-naphthaldehyde (6.5 mg, 34.4 mg theoretical, 18.8%). LC-MS m/z 478.3 (M+1).

Example 59

(Z)-5-((2-((trans-4-(((2′-methoxy-[1,1′-biphenyl]-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2′-methoxy-[1,1′-biphenyl]-2-carbaldehyde (12.9 mg, 37.1 mg theoretical, 34.7%). LC-MS m/z 516.6 (M+1).

Example 60

(Z)-5-((2-((trans-4-(((4′-fluoro-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4′-fluoro-[1,1′-biphenyl]-3-carbaldehyde (2.3 mg, 36.3 mg theoretical, 6.3%). LC-MS m/z 504.5 (M+1).

Example 61

(Z)-5-((2-((trans-4-(((6-bromonaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-bromo-2-naphthaldehyde (2.8 mg, 38.8 mg theoretical, 7.2%). LC-MS m/z 539.5 (M+1).

Example 62

(Z)-5-((2-((trans-4-(((2-(1H-pyrazol-5-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(1H-pyrazol-5-yl)nicotinaldehyde (2.3 mg, 33 mg theoretical, 7%). LC-MS m/z 477.5 (M+1).

Example 63

(Z)-5-((2-((trans-4-((4-fluorophenethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(4-fluorophenyl)acetaldehyde (2.5 mg, 30.6 mg theoretical, 8.2%). LC-MS m/z 442.5 (M+1).

Example 64

(Z)-5-((2-((trans-4-((2-fluoro-3-(trifluoromethyl)phenethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetaldehyde (5.4 mg, 36.7 mg theoretical, 15%). LC-MS m/z 510 (M+1).

Example 65

(Z)-5-((2-((trans-4-(((2-(1H-pyrrol-2-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(1H-pyrrol-2-yl)nicotinaldehyde (2.1 mg, 32.9 mg theoretical, 6.4%). LC-MS m/z 476.5 (M+1).

Example 66

(Z)-5-((2-((trans-4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-(thiophen-3-yl)picolinaldehyde (5.0 mg, 35.0 mg theoretical, 14%). LC-MS m/z 507 (M+1).

Example 67

(Z)-5-((2-((trans-4-(((2-methylpyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-methylnicotinaldehyde (7.2 mg, 29.4 mg theoretical, 24.5%). LC-MS m/z 425.5 (M+1).

Example 68

(Z)-5-((2-(((trans-4-((phenethylamino)methyl)cyclohexyl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-phenylacetaldehyde (2.3 mg, 30.3 mg theoretical, 8%). LC-MS m/z 452 (M+1).

Example 69

(Z)-5-((2-((trans-4-((phenethylamino)methyl)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-phenylacetaldehyde (1.6 mg, 30.2 mg theoretical, 5%). LC-MS m/z 438 (M+1).

Example 70

(Z)-5-((2-((trans-4-(((4-fluoro-2-(furan-2-yl)benzyl)amino)methyl)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-fluoro-2-(furan-2-yl)benzaldehyde (1.3 mg, 35 mg theoretical, 3%). LC-MS m/z 508 (M+1).

Example 71

(Z)-5-((2-((trans-4-((3-(furan-2-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 3-(furan-2-yl)benzaldehyde (11.6 mg, 32.9 mg theoretical, 35.2%). LC-MS m/z 476.5 (M+1).

Example 72

(Z)-5-((2-((trans-4-((4-fluoro-2-(thiophen-2-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-fluoro-2-(thiophen-2-yl)benzaldehyde (13 mg, 35.5 mg theoretical, 37%). LC-MS m/z 510.6 (M+1).

Example 73

(Z)-5-((2-((trans-4-((4-fluoro-2-(thiophen-3-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-fluoro-2-(thiophen-3-yl)benzaldehyde (17.2 mg, 35.5 mg theoretical, 48.8%). LC-MS m/z 510.6 (M+1).

Example 74

(Z)-5-((2-((trans-4-((4-fluoro-2-(furan-3-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-fluoro-2-(furan-3-yl)benzaldehyde (10.2 mg, 20.7 mg theoretical, 49.1%). LC-MS m/z 494.5 (M+1).

Example 75

(Z)-5-((2-((trans-4-(((2-methoxynaphthalen-1-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-methoxy-1-naphthaldehyde (11 mg, 33.9 mg theoretical, 32.5%). LC-MS m/z 490.5 (M+1).

Example 76

(Z)-5-((2-((trans-4-((2-(pyridin-3-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(pyridin-3-yl)benzaldehyde (9 mg, 33.7 mg theoretical, 26.7%). LC-MS m/z 487.5 (M+1).

Example 77

(Z)-5-((2-((trans-4-(((4-(dimethylamino)naphthalen-1-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-(dimethylamino)-1-naphthaldehyde (14.4 mg, 34.8 mg theoretical, 41.4%). LC-MS m/z 503.6 (M+1).

Example 78

(Z)-5-((2-(((trans-4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)cyclohexyl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 3-(thiophen-3-yl)benzaldehyde (3.9 mg, 34.9 mg theoretical, 11%). LC-MS m/z 521 (M+1).

Example 79

(Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared as follows. A 40 mL round bottomed vial was charged with (Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (203 mg, 0.712 mmol), DMSO (3 mL), ammonium acetate (543 mg, 7.04 mmol, 10 equiv.) and heated at 100° C. for 2 h. The reaction was concentrated under reduced pressure using the Genevac. The residue was partitioned between 3 mL of DCE and 3 mL of H₂O and the aqueous layer was back extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure to provide the desired product. (114 mg, 0.477 mmol, 67.0% yield). LC-MS m/z 223 (M+1).

Example 80

(Z)-5-((2-((3-methoxypheny)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 3-methoxyaniline (3.1 mg, 28.8 mg theoretical, 10.8%). LC-MS m/z 329 (M+1).

Example 81

(Z)-5-((2-(phenylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and aniline (3.2 mg, 26.1 mg theoretical, 12%). LC-MS m/z 299 (M+1).

Example 82

(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)furan-2-carboxamide was prepared as follows. A 2-dram vial charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (30.4 mg, 0.137 mmol), Pyridine (1.1 mL), furan-2-carbonyl chloride (107 mg, 0.821 mmol, 6 equiv.), triethylamine (83 mg, 0.821 mmol, 6 equiv.), and shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (14 mg, 43.3 mg theoretical, 32.4%). LC-MS m/z 317.3 (M+1).

Example 83

(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)quinoline-2-carboxamide was prepared as follows. A 2-dram vial was charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg, 0.100 mmol), Pyridine (1 mL), quinoline-2-carbonyl chloride (74.6 mg, 0.389 mmol, 3.8 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9 equiv.), and the reaction was shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (3 mg, 37.7 mg theoretical, 8%). LC-MS m/z 378.4 (M+1).

Example 84

(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-5-(trifluoromethyl)picolinamide was prepared as follows. A 2-dram vial was charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg, 0.100 mmol), Pyridine (1 mL), 5-(trifluoromethyl)picolinoyl chloride (63 mg, 0.301 mmol, 3 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9 equiv.), and the reaction was shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (4 mg, 39.5 mg theoretical, 10%). LC-MS m/z 396.3 (M+1).

Example 85

(((trans-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)((6-(thiophen-3-yl)pyridin-2-yl)methyl)carbamoyl)oxy)methyl acetate

(Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione trifluoroacetate salt (73.6 mg, 0.12 mmol, 1 equiv.) was dissolved in DMF (2 mL) and DIEA (63 μL, 0.36 mmol, 3 equiv.) was added at once. Chloromethyl chloroformate (10.7 μL, 0.12 mmol, 1.0 equiv.) was added at once and the reaction mixture was stirred at RT for 1 h. Silver acetate (61 mg, 0.36 mmol, 3 equiv.) was added at once and the reaction mixture was shaken for 1 h at 85° C. The desired carbamate was purified by preparative HPLC (TFA method). The purest fractions were pooled and evaporated. The residue was re-dissolved in a 1:1 mixture of methanol/1% NH₄OH aqueous solution and the solvents were evaporated under reduced pressure. The free base was purified on silica gel (CH₂Cl₂/MeOH 95:5) to give the desired product as a yellow solid (1.1 mg, 73.7 mg theoretical, 1.5%). LC-MS m/z 609 (M+1).

Example 86

((Z)-5-((2-(((1s,4s)-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl dihydrogen phosphate

An 8 mL round bottomed vial was charged with boc-protected amine [sad123-119] (34.5 mg, 46 μmol., 1 equiv.), CH₂Cl₂ (0.5 mL), and TFA (175 μL, 2.28 mmol, 50 equiv.). The solution was stirred for 15 min at RT. LC-MS showed the reaction was complete. The solvents were concentrated under reduced pressure. The residue was dissolved in DMSO and purified by revers phase HPLC (0-50, 12 min, 2 inj) to provide 18.3 mg (73.8%, 1 TFA salt) of the desired product as a white solid. LC-MS: 0.58 min, M+1=430.

Example 87

(Z)-5-((2-((1r,4r)-4-((((6-fluoronaphthalen-2-yl)methyl)amino)methyl)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-fluoro-2-naphthaldehyde (2.4 mg, 23.9 mg theoretical, 7%). LC-MS m/z 492.5 (M+1).

Example 88

(Z)-5-((2-(((1r,4r)-4-(((2-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-(2,2,2-trifluoroethoxy)nicotinaldehyde (6.7 mg, 35.5 mg theoretical, 19%). LC-MS m/z 509.5 (M+1).

Example 89

(Z)-5-((2-(((1r,4r)-4-(((5-fluoro-2-methoxypyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 5-fluoro-2-methoxynicotinaldehyde (4.3 mg, 31.7 mg theoretical, 13.5%). LC-MS m/z 459.5 (M+1).

Example 90

(Z)-5-((2-(((1r,4r)-4-(((2-methoxypyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-methoxynicotinaldehyde (9.3 mg, 30.5 mg theoretical, 30.5%). LC-MS m/z 441.5 (M+1).

Example 91

(Z)-5-((2-(((1r,4r)-4-(((2-fluoropyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-fluoronicotinaldehyde (13.1 mg, 29.7 mg theoretical, 44%). LC-MS m/z 429.5 (M+1).

Example 92

(Z)-5-((2-(((1r,4r)-4-((pyridin-3-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and nicotinaldehyde (3.7 mg, 38.6 mg theoretical, 10%). LC-MS m/z 411 (M+1).

Example 93

(Z)-5-((2-(((1r,4r)-4-((benzofuran-5-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and benzofuran-5-carbaldehyde (4.6 mg, 42.2 mg theoretical, 10%). LC-MS m/z 450.5 (M+1).

Example 94

(Z)-5-((2-(((1r,4r)-4-(((4-chloropyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-chloronicotinaldehyde (3 mg, 42 mg theoretical, 7%). LC-MS m/z 446 (M+1).

Example 95

(Z)-5-((2-(((1r,4r)-4-(((6-hydroxypyridazin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 6-hydroxypyridazine-3-carbaldehyde (6.8 mg, 40.2 mg theoretical, 17%). LC-MS m/z 428 (M+1).

Example 96

(Z)-5-((2-(((1r,4r)-4-((quinolin-8-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and quinoline-8-carbaldehyde (2.1 mg, 43.3 mg theoretical, 4.8%). LC-MS m/z 461 (M+1).

Example 97

(Z)-5-((2-(((1r,4r)-4-(((4-(furan-3-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-(furan-3-yl)nicotinaldehyde (14.6 mg, 44.8 mg theoretical, 32%). LC-MS m/z 477 (M+1).

Example 98

(Z)-5-((2-(((1r,4r)-4-((pyrimidin-5-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and pyrimidine-5-carbaldehyde (23.3 mg, 48.7 mg theoretical, 60%). LC-MS m/z 412 (M+1).

Example 99

(Z)-5-((2-(((1r,4r)-4-(((2-fluoro-4-(furan-3-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 2-fluoro-4-(furan-3-yl)nicotinaldehyde (17 mg, 46.5 mg theoretical, 37%). LC-MS m/z 495 (M+1).

Example 100

(Z)-5-((2-(((1r,4r)-4-(((4-methoxypyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 4-methoxynicotinaldehyde (21 mg, 41.4 mg theoretical, 51%). LC-MS m/z 441 (M+1).

Example 101

(Z)-5-((2-(((1r,4r)-4-((isoquinolin-4-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and isoquinoline-4-carbaldehyde (27.9 mg, 44.3 mg theoretical, 64.5%). LC-MS m/z 461 (M+1).

Example 102

N-((1r,4r)-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)quinoline-8-sulfonamide was prepared using the General Procedure for the Preparation of Sulfonamides/Amides and quinoline-8-sulfonyl chloride (6.6 mg, 80 mg theoretical, 8.3%). LC-MS m/z 511.5 (M+1).

Example 103

N-((1r,4r)-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)quinoline-8-carboxamide was prepared using the General Procedure for the Preparation of Sulfonamides/Amides and quinoline-8-carbonyl chloride (6.8 mg, 44.6 mg theoretical, 15.3%). LC-MS m/z 475.5 (M+1).

Example 104

N-((1r,4r)-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)furan-2-carboxamide was prepared using the General Procedure for the Preparation of Sulfonamides/Amides and furan-2-carbonyl chloride (8.9 mg, 38.8 mg theoretical, 23%). LC-MS m/z 414 (M+1).

Example 105

N-((1r,4r)-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)furan-2-sulfonamide was prepared using the General Procedure for the Preparation of Sulfonamides/Amides and furan-2-sulfonyl chloride (7 mg, 70.7 mg theoretical, 10%). LC-MS m/z 450.5 (M+1).

Example 106

(Z)-5-((2-(((1r,4r)-4-aminocyclohexyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl ((1r,4r)-4-(methylamino)cyclohexyl)carbamate followed by the general de-protection procedure (2.5 mg, 23.3 mg theoretical, 10%). LC-MS m/z 334 (M+1).

Example 107

(Z)-5-((2-(methyl((1r,4r)-4-((naphthalen-1-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general reductive amination procedure 1 and 1-naphthaldehyde (5.4 mg, 42.3 mg theoretical, 13%). LC-MS m/z 474.5 (M+1).

Prophetic Reductive Amination Analogs (Some Syntheses Completed)

Example 108

(Z)-5-((2-((trans-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl (trans-4-aminocyclohexyl)carbamate followed by the general de-protection procedure (6.3 mg, 8.9 mg theoretical, 70%). LC-MS m/z 320 (M+1).

Example 109

(Z)-5-((2-((cis-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl (cis-4-aminocyclohexyl)carbamate followed by the general de-protection procedure (17 mg, 15.2 mg theoretical, 112%). LC-MS m/z 320 (M+1).

Example 110

(Z)-5-((2-((trans-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and tert-butyl ((trans-4-aminocyclohexyl)methyl)carbamate followed by the general de-protection procedure (5.6 mg, 6.15 mg theoretical, 91%). LC-MS m/z 334 (M+1).

Example 111

(Z)-5-((2-((4-morpholinophenyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and 4-morpholinoaniline (2 mg, 33.6 mg theoretical, 6%). LC-MS m/z 384 (M+1).

Example 112

N-(trans-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)furan-2-carboximidamide was prepared as follows.

Preparation of Methyl Furan-2-Carbimidate Hydrochloride

A 30 mL scintillation vial was charged with furan-2-carbonitrile (107 mg, 1.15 mmol), methanol (1 mL), and 4.0 M HCl in dioxane (2 mL, 8.00 mmol, 6.95 equiv.). The reaction was shaken at room temperature overnight. LCMS showed a predominant peak for M+1=126, methyl furan-2-carbimidate. The solvent was evaporated under reduced pressure and the material was used directly in the next step without further purification.

A 2-dram round botommed vial was charged with methyl furan-2-carbimidate hydrochloride (14.5 mg, 0.090 mmol), DMSO (0.5 mL), (Z)-5-((2-((trans-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (27.2 mg, 0.085 mmol) (prepared using the general displacement procedure and tert-butyl ((1R,4R)-4-aminocyclohexyl)carbamate followed by the general de-protection procedure), MeOH (0.25 mL) was then added and the mixture shaken until homogeneous. The solution was then treated with N-ethyl-N-isopropylpropan-2-amine (250 mg, 1.934 mmol, 21.5 equiv.), purged with Ar, capped and shaken overnight at room temperature. (8.4 mg, 35.1 mg theoretical, 23.9%). LC-MS m/z 413 (M+1).

Example 113

(Z)-5-((2-((trans-4-((2-(2-methoxyethoxyl)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared as follows. Synthesis of trans-N1-(2-(2-methoxyethoxyl)ethyl)cyclohexane-1,4-diamine bis trifluoroacetic acid salt

2-(2-Methoxyethoxyl)ethyl 4-methylbenzenesulfonate: A solution of 2-(2-methoxyethoxyl)ethanol (200 mg, 1.67 mmol, 1 equiv.), triethylamine (232 μL, 1.67 mmol, 1.0 equiv.) and tosyl chloride (317 mg, 1.67 mmol, 1 equiv.) in methylene chloride (5 mL, 0.29 M) was stirred at room temperature for 50 hours. After removal of the solvent under reduced pressure, the residue was purified by chromatography on silica gel (10 g, hexanes/EtOAc 9:1 to 1:1) to afford (2-methoxyethoxy)ethyl 4-methylbenzenesulfonate as a colorless oil (260 mg, 457 mg theoretical, 56.9%). LC-MS m/z 275 (M+1).

tert-Butyl (trans-4-((2-(2-methoxyethoxy)ethyl)amino)cyclohexyl)carbamate

A solution of (2-methoxyethoxy)ethyl 4-methylbenzenesulfonate (160 mg, 0.58 mmol, 1 equiv.), DIEA (102 μL, 0.58 mmol, 1.0 equiv.) and tert-butyl (trans-4-aminocyclohexyl)carbamate (125 mg, 0.58 mmol, 1 equiv.) in acetonitrile (2.5 mL, 0.23 M) was stirred at 85° C. for 50 minutes. After removal of the solvent under reduced pressure, the residue was purified by preparative HPLC (H₂O/MeOH 0.1% TFA) to afford tert-butyl (trans-4-((2-(2-methoxyethoxy)ethyl)amino)cyclohexyl)carbamate trifluroacetate salt as a colorless oil (114 mg, 251 mg theoretical, 45.4%). LC-MS m/z 317 (M+1), 275 (M+1-isobutylene).

Synthesis of trans-N1-(2-(2-methoxyethoxyl)ethyl)cyclohexane-1,4-diamine bis trifluoroacetate salt

A solution of tert-butyl (trans-4-((2-(2-methoxyethoxyl)ethyl)amino)cyclohexyl)carbamate trifluroacetate salt (114 mg, 0.27 mmol, 1 equiv.) in TFA (1.38 mL, 18.0 mmol, 68.0 equiv.) and methylene chloride (1.5 mL, 0.09 M) was stirred at RT for 1 hour. After removal of the solvent under reduced pressure, the residue was triturated in ether to afford trans-N1-(2-(2-methoxyethoxyl)ethyl)cyclohexane-1,4-diamine bis trifluoroacetate salt as a white solid (77.7 mg, 118 mg theoretical, 66.0%). LC-MS m/z 217 (M+1).

(Z)-5-((2-((trans-4-((2-(2-methoxyethoxyl)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using the general displacement procedure and trans-N1-(2-(2-methoxyethoxyl)ethyl)cyclohexane-1,4-diamine bis trifluoroacetate salt (4.1 mg, 56.3 mg theoretical, 7.3%). LC-MS m/z 422 (M+1).

Example 114 Prophetic Prodrug Analogs

Example 115

((Z)-5-((2-(((1s,4s)-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl dihydrogen phosphate

tert-butyl (trans-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate trifluoroacetate salt (70.8 mg, 0.13 mmol, 1 equiv.) is dissolved in DMF (1 mL) and sodium hydride 60% in mineral oil (63 μL, 0.36 mmol, 3 equiv.) is added at once. Chloromethyl chloroformate (10.6 mg, 0.26 mmol, 2.0 equiv.) is added at once and the reaction mixture is stirred at RT for 45 min. di-tert-Butyl (chloromethyl) phosphate (31 μL, 0.13 mmol, 1 equiv.) is added at once and the reaction mixture is shaken for 1 h at RT. The reaction mixture is then shaken at 50° C. The solvent is evaporated and the residue is suspended in CH₂Cl₂ and treated with trifluoroacetic acid (0.26 mL, 3.33 mmol, 25 equiv). The desired phosphate is purified by preparative HPLC (Basic method).

Example 116

((Z)-2,4-dioxo-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidin-3-yl)methyl dihydrogen phosphate

((Z)-2,4-dioxo-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidin-3-yl)methyl dihydrogen phosphate is prepared by boc-protecting the secondary amine of (Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino) pyrimidin-4-yl)methylene)thiazolidine-2,4-dione followed by the alkylation of the hydantoin with di-tert-butyl chloromethylphosphate and the deprotection of the t-butyl groups and the boc group with TFA.

Example 117 General Boronic Acid Coupling Procedures for the Synthesis of Custom Aldehydes

A 2-dram round bottomed vial was charged with 6-bromopicolinaldehyde (100 mg, 0.538 mmol) and the boronic acid (0.538 mmol, 1 equiv.) were added in THF (2 mL). Then 2 M Na₂CO₃ (0.403 mL, 0.806 mmol, 1.5 equiv.) and Pd(Ph₃P)₄ (31.0 mg, 0.027 mmol, 0.05 equiv.) were added and shaken at 85° C. overnight. The solvent was removed in the genevac and the residue was washed with saturated NaHCO₃ (1 mL). The aqueous layer was extracted with EtOAc (3×1 mL). The combined organic layers were dried on the genevac and the crude was purified using flash purification with a gradient of 5-40% EtOAc in hexane.

General Boronic Acid Coupling Procedures for the Synthesis of Custom Ketones

A 40 mL round bottomed vial was charged with 1-(6-bromopyridin-2-yl)ethanone (780 mg, 3.9 mmol), THF (96 mL, 0.48 M), the boronic acid (3.9 mmol, 1.0 equiv.), 2 M Na₂CO₃ (3.9 mL, 7.8 mmol, 2.0 equiv.), Pd(Ph₃P)₄ (225 mg, 0.195 mmol, 0.05 equiv.), purged with Ar, and shaken at 85° C. for 36 h. The solvent was removed in the genevac and the residue was partitioned between saturated NaHCO₃ (25 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The crude material was purified on the Biotage (SiO₂, 50 g, 2-50% EtOAc/hexanes over 30 column volumes) to afford the desired coupled products.

Example 118 Assays

Selected Cell Proliferation Inhibition Data

TABLE 1 Human Positive Incubation cancer Cell line Medium drug time Multiple MV4-11 IMDM Cisplatin 72 hours Myeloma RPMI-8226 RPMI-1640 NCI-H929 RPMI-1640 + 0.05 mM 2- mercaptoethanol

All cells were cultured in media supplemented with 10% FBS except for which are marked specially, in the temperature of 37° C., 5% CO₂ and 95% humidity. All culture media were purchased from GIBCO (USA, IMDM Cat. 12200-036; RPMI Medium 1640 Cat. 31800-022; 2-mercaptoethanol Cat. 21985-023).

Reagents:

CellTiter 96® Aqueous MTS reagent powder (Cat. No.: G11 12, Promega. Store MTS Reagent Powder desiccated at 4° C. protected from light.)

Phenazine methosulfate (PMS) (Product No.: P9625, SIGMA. Store PMS Powder desiccated at 4° C. protected from light.)

Preparation of PMS Solution:

0.92 mg/mL PMS in DPBS Filter-sterilize through a 0.2 μm filter into a sterile, light-protected container. Store at −20° C.

Preparation of MTS Solution:

The following protocol is recommended for the preparation of 21 mL of MTS solution (sufficient for ten 96-well plates).

-   a. Select a light-protected container or wrap a container with foil. -   b. Add 21 mL of DPBS to the container. -   c. Weigh out 42 mg of MTS Reagent Powder and add to DPBS. -   d. Mix at moderate speed on a magnetic stir plate for 15 minutes or     until the MTS is completely dissolved. -   e. Measure the pH of the MTS solution. The optimum pH is between pH     6.0 to 6.5. If the solution is above pH 6.5, adjust to pH 6.5 with     1N HCl. -   f. Filter-sterilize the MTS solution through a 0.2 μm filter into a     sterile, light protected container. -   g. Store the MTS solution at −20° C., protected from light.     Preparation of the Mixture of MTS/PMS: -   a. In order to prepare reagents sufficient for one 96-well plate     containing cells cultured in a 100 μL volume, thaw the MTS solution     and the PMS solution. It should take approximately 90 minutes at     room temperature or 10 minutes in a 37° C. water bath to completely     thaw the 20 mL size of MTS solution. (Note: For convenience, the     first time the product is thawed, the entire contents of the 1 mL     tube of PMS solution can be transferred to the 20 mL bottle of MTS     solution. This mixture should be stored at −20° C. between uses. If     storing PMS and MTS solutions at 4° C., do not combine these     solutions until immediately before addition to the assay plate.) -   b. Remove 2.0 mL of MTS solution from the amber reagent bottle using     aseptic technique and transfer to a test tube. -   c. Add 100 μL of PMS solution to the 2.0 mL of MTS solution     immediately before addition to the culture plate containing cells. -   d. Gently swirl the tube to ensure complete mixing of the combined     MTS/PMS solution.     Equipment:

SpectraMAX plus microplate spectrophotometer Model 3011, Molecular Devices Corp. (California, USA); CO₂ water jacketed incubator, Therma (USA). Reverse microscope, Chongguang XDS-1B, Chongqing Guangdian Corp. (Chongqing, P.R. China).

Cytotoxicity and IC₅₀ Determination:

-   1. The cells were harvested respectively during the logarithmic     growth period and counted with hemocytometer. The cell viability was     over 98% by trypan blue exclusion. -   2. Cell concentrations were adjusted to 2.22×113 or 1.11×113 or     5.56×10⁴ cells/mL with respective medium. -   3. 90 μL cell suspensions were added to 96-well plates (triplicates     for each cell concentration), the final cell densities were 2×10⁴ or     1×10⁴ or 5×10³ cells/well. The density of 5×10³ cells/well was used     for the first test. The appropriate cell density was determined and     adjusted according to the results of the first test. -   4. The next day, test article or positive drugs were dissolved with     DMSO as stock solution at the concentration of 20 mM. -   5. 10 μL drug solution was dispensed in each well (triplicate for     each drug concentration). -   6. Plates were cultured for another 72 hours, then measured by means     of MTS assay. -   7. MTS/PMS solution was prepared immediately prior to use. 20 μL of     the mixture was introduced into each well of the 96-well assay plate     containing 100 μL culture medium. (The final reaction volume was 120     μL). -   8. Plate was incubated for 1-4 hours at 37° C. in a humidified 5%     CO₂ atmosphere. -   9. Absorbance at 490 nm was recorded using SpectraMAX Plus     microplate spectrophotometer.     Data Analysis:

The software of GraphPad Prism version 5 was used to calculate IC₅₀. The graphical curves were fitted using a nonlinear regression model with a sigmoidal dose.

Results

Results are shown in Table 2.

TABLE 2 IC₅₀ values (μM) Cmpd Panc-1 RPMI-8226 KU812 NCI-H929 MV4-11 11219 >50 18 >50 17.1 11231 32 21.4 >50 10.8 11233 27 14.1 6.7 35 11238 11.5 3.2 11.8 2.1 11239 18.1 2.2 23.5 3.2 11252 >50 >50 >50 27.4 11253 >50 41 >50 16.2 11254 >50 >50 >50 33.4 11255 5.3 2.6 2.1 0.55 0.42 11256 15.7 8.6 19.4 7.2 11270 5.6 1.8 2.5 0.64 0.7 11292 >50 >50 11294 27 28 11302 36.9 14.3 11305 2.7 1.2 11353 7.4 10.4 11405 0.91 1 11407 1 1.1 11408 1.5 1.4 11409 0.93 1.2 11410 1.9 2.3 11412 1.1 1.2 11413 0.73 0.55 0.59 0.54 11414 0.58 0.29 11415 1.1 1.4 11416 0.11 0.13 0.23 0.085 11417 3.4 1.8 11421 4.3 1.9 11422 5.1 3.3 11423 15.3 4.1 11406 2.9 7.4 11411 2.6 18.8 11533 29.1 >50 11534 1.1 10.2 11535 0.67 5.3 11536 1.4 2.7 11432 0.92 3.2 11644 0.062 0.11 0.086 0.037 11645 2.7 1.7 11646 0.091 0.031 11647 1.4 2.3 11648 4.8 3.6 11649 2.1 1.9 11650 0.66 1.5 11651 >50 6.8 11652 0.35 0.34 11653 >50 7.6 11654 1.6 6.3 11655 5.2 4.7 11656 2.3 11657 1.3 5.3 11658 0.3 1 11659 7 4.7 11660 0.77 0.4 0.24 11661 1.5 1.1 11662 0.082 0.14 0.084 0.1 11663 2.4 2.1 11664 3.7 4.5 11665 4 0.98 11669 18.2 18.4 11670 10.3 9.8 11671 0.8 1.4 11672 1.2 1.4 11673 0.2 0.33 11674 3.5 3.3 11675 4.6 1.6 11676 0.93 1.2 11677 1.2 1.7 11678 0.69 0.76 11723 21 14 11712 4.2 4 11717 0.55 1.1 11739 3.4 3.9 11740 5.5 4.4 11741 4.6 4.2 11801 3.9 3.5 11802 0.49 0.16 0.097 11816 3.4 0.34 0.38 11834 >50 >50 11835 4.7 1.3 11836 10.1 0.65 11837 >50 3 11838 >50 4.6 11839 >50 11.8 11840 1.5 0.37

TABLE 3 Percent Activity of Enzyme When Treated with 300 nM of Compound (ATP present at Km of enzyme) Pim- Pim- Pim- Cmpd CK1γ2(h) CK1(y) CK2(h) 1(h) 2(h) 3(h) 11219 64 63 10 23 3 5 11231 113 92 10 50 58 42 11233 97 64 80 100 99 91 11238 48 61 14 52 42 32 11239 52 91 21 56 37 33 11252 96 96 20 86 110 83 11253 101 93 68 99 55 96 11254 96 107 86 113 97 113 11255 14 46 16 15 1 7 11256 44 58 30 26 2 4 11270 25 59 32 19 1 5 11292 45 77 11 14 −1 3 11294 87 72 32 35 4 5 11302 98 82 12 12 3 3 11305 71 86 11 22 6 8 11353 43 50 12 18 −1 4 11405 −6 18 −1 8 −2 0 11407 53 48 −7 10 −1 0 11408 7 43 5 12 1 3 11409 54 41 −11 11 0 2 11410 77 74 −12 21 −1 0 11412 22 49 14 11 −1 0 11413 38 62 −16 7 0 2 11414 25 42 20 18 0 1 11415 6 35 −5 11 −1 1 11416 19 48 −9 7 −1 0 11417 57 55 6 14 0 0 11421 98 97 8 32 3 2 11422 79 97 49 78 15 25 11423 98 99 46 49 8 8 11406 −10 44 25 14 5 3 11411 43 52 76 28 0 12 11533 109 80 63 46 7 6 11534 72 59 21 14 −1 2 11535 35 51 14 14 −1 1 11536 31 84 64 44 2 9 11432 12 47 16 16 1 6 11644 13 57 −3 10 1 5 11645 29 45 −19 3 0 2 11646 22 56 −15 7 1 2 11647 9 35 −18 7 1 6 11648 −2 41 15 28 2 21 11649 5 37 −15 5 0 1 11650 9 51 −3 14 0 4 11651 55 71 1 22 −1 3 11652 17 50 −6 16 0 5 11653 33 52 26 21 1 5 11654 63 67 −10 19 3 2 11655 14 67 54 34 1 16 11656 65 75 −6 20 −1 1 11657 23 39 29 35 2 2 11658 6 30 19 13 1 1 11659 9 37 −6 9 −2 1 11660 40 58 −14 11 −2 2 11661 −3 32 −17 9 −3 −1 11662 16 52 −14 9 −2 −2 11663 25 54 1 12 −2 −1 11664 5 39 1 19 −2 −1 11665 14 52 9 20 −2 3 11669 77 80 −6 16 1 3 11670 74 86 46 48 7 10 11671 28 50 23 16 2 4 11672 31 40 −6 14 0 3 11673 5 19 −2 11 1 2 11674 72 65 −12 10 0 2 11675 82 77 −11 18 18 11 11676 32 49 −10 11 2 3 11677 21 47 0 20 4 6 11678 −4 41 −18 6 −1 2 11679 27 43 −6 9 0 3 11680 24 35 −11 7 0 2 11681 23 44 −13 10 −1 4 11682 29 54 −18 10 −1 1 11683 50 62 −6 12 −1 2 11684 41 58 −12 5 −1 2 11685 98 95 95 119 103 89 11686 46 68 38 17 12 22 11536 31 84 64 44 2 9 11723 63 78 −15 23 0 4 11712 −1 25 −6 11 2 4 11717 43 50 −16 15 0 2 11739 63 78 −15 23 0 4 11740 62 67 −17 18 −2 6 11741 48 68 −14 17 0 6 11801 72 66 1 19 −2 3 11802 27 56 −3 7 −2 3 11816 38 46 −4 8 −2 1 11834 76 70 11 20 −3 2 11835 49 73 2 13 −6 2 11836 41 56 7 14 −5 2 11837 71 57 16 19 −6 2 11838 32 55 5 20 −6 1 11839 69 55 −1 16 −6 −1 11840 37 48 −5 11 −8 −1 12040 −3 −1 0 12054 −2 −3 0 12078 19 −1 2

TABLE 4 IC₅₀ (nM) (ATP present at Km of enzyme) Pim- Pim- Pim- Cmpd CK1γ2(h) CK1(y) CK2(h) 1(h) 2(h) 3(h) 11219 204 7 27 11231 72 11233 11238 69 11239 87 11252 61 11255 12 0.5 4 11256 123 1 15 11270 187 3 32 11292 69 78 1 9 11294 247 18 113 11407 33 0.6 3 11409 103 1 4 11410 108 1 9 11413 9 38 0.6 9 11414 85 2 5 11416 29 36 1 6 11417 42 2 4 11644 45 32 0.7 6 11646 6 24 0.5 1 11650 29 68 2 12 11652 24 67 0.7 16 11660 11 42 2 4 11662 6 50 9 4 11673 28 96 4 18 11674 11 79 0.7 5 11923 377 160 205 11932 1231 6 260 11933 330 11 26 11934 118 10 14 12054 82 29 1 7

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. published patent applications cited herein are hereby incorporated by reference.

EQUIVALENTS

While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention. 

We claim:
 1. A method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence: X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃—R₆; R′ is H, methyl, (C₂-C₄)alkyl, or benzyl; R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂, —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂; R₃ is —C(═NR)— or —(C(R)₂)_(n)—; R₅ is selected from the group consisting of 1,4-cyclohexanediyl, 1,4-phenylene, 1,4-cycloheptanediyl, 1,4-cyclooctanediyl, 1,5-cyclooctanediyl, bicyclo[2.2.1]heptanediyl, 1,4-bicyclo[2.2.2]octanediyl, and 1,5-bicyclo[3.3.1]nonanediyl; R₆ is selected from the group consisting of alkyl, alkylaryl, aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of which is optionally mono or di-substituted, and the substituents, if present, are independently selected from the group consisting of alkyl, alkylaryl, aralkyl, aryl, heteroaryl, alkoxy, hydroxy, perfluoroalkyl, trifluoromethoxy, and halide, wherein the optional aryl or heteroaryl substituent may be optionally substituted with alkyl, halide, alkoxy, perfluoroalkyl, or dioxolanyl; R₇ is selected from the group consisting of H, —C(═NR)R, —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of which is optionally mono or di-substituted, and the substituents, if present, are independently selected from the group consisting of alkyl, alkylaryl, aralkyl, aryl, heteroaryl, alkoxy, hydroxy, perfluoroalkyl, trifluoromethoxy, and halide, wherein the optional aryl or heteroaryl substituent may be optionally substituted with alkyl, halide, alkoxy, perfluoroalkyl, or dioxolanyl, or two instances of R₇ and the nitrogen to which they are bonded taken together represent a nitrogen-containing heterocyclyl, optionally containing one additional heteroatom in the ring, wherein said additional heteroatom is selected from the group consisting of —O—, —N(R)—, and —S—; R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl; R is H or (C₁-C₄)alkyl; and n is 1, 2 or 3; wherein the cancer is selected from the group consisting of: adrenocortical carcinoma; anal cancer; basal cell carcinoma; bladder cancer; breast cancer; bronchial adenomas/carcinoids; cervical cancer; colon cancer; colorectal cancer; endometrial cancer; esophageal cancer; extrahepatic bile duct cancer; gallbladder cancer; gastric (stomach) cancer; gastrointestinal carcinoid tumor; gestational trophoblastic tumor; head and neck cancer, hepatocellular (liver) cancer; hypopharyngeal cancer; kidney (renal cell) cancer; laryngeal cancer; lip and oral cavity cancer; metastatic squamous neck cancer with occult primary; multiple endocrine neoplasia syndrome; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer; Non-Small Cell Lung cancer; oral cancer; oropharyngeal cancer; pancreatic cancer; parathyroid cancer; penile cancer; pituitary tumor; prostate cancer; rectal cancer; salivary gland cancer; skin carcinoma, Merkel Cell; small cell lung cancer; small intestine cancer; squamous cell carcinoma; thymoma; thymoma and thymic carcinoma; thyroid cancer; transitional cell cancer of the renal pelvis and ureter; urethral cancer; uterine cancer, endometrial; vaginal cancer; vulvar cancer; Wilms' Tumor; acute lymphoblastic leukemia; acute myeloid leukemia; AIDS-related lymphoma; Burkitt's lymphoma; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; cutaneous T-cell lymphoma; hairy cell leukemia; hematologic (blood) cancer; Hodgkin's lymphoma; multiple myeloma/plasma cell neoplasm' mycosis fungoides; myelodysplastic syndromes; myelodysplastic/myeloproliferative diseases; multiple myeloma; Non-Hodgkin's lymphoma; primary central nervous system lymphoma; Sezary Syndrome; Waldenstrom's Macroglobulinemia; Ewing's sarcoma; Kaposi's Sarcoma; osteosarcoma/malignant fibrous histiocytoma of bone; soft tissue sarcoma; uterine sarcoma; extracranial germ cell tumor; extragonadal germ cell tumor; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; and testicular cancer.
 2. A method of increasing the rate of apoptosis in cancerous cells in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof:

wherein independently for each occurrence: X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃—R₆; R′ is H, methyl, (C₂-C₄)alkyl, or benzyl; R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂, —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂; R₃ is —C(═NR)— or —(C(R)₂)_(n)—; R₅ is selected from the group consisting of 1,4-cyclohexanediyl, 1,4-phenylene, 1,4-cycloheptanediyl, 1,4-cyclooctanediyl, 1,5-cyclooctanediyl, 1,4-bicyclo[2.2.1]heptanediyl, 1,4-bicyclo[2.2.2]octanediyl, and 1,5-bicyclo[3.3.1]nonanediyl; R₆ is selected from the group consisting of alkyl, alkylaryl, aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of which is optionally mono or di-substituted, and the substituents, if present, are independently selected from the group consisting of alkyl, alkylaryl, aralkyl, aryl, heteroaryl, alkoxy, hydroxy, perfluoroalkyl, trifluoromethoxy, and halide, wherein the optional aryl or heteroaryl substituent may be optionally substituted with alkyl, halide, alkoxy, perfluoroalkyl, or dioxolanyl; R₇ is selected from the group consisting of H, —C(═NR)R, —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of which is optionally mono or di-substituted, and the substituents, if present, are independently selected from the group consisting of alkyl, alkylaryl, aralkyl, aryl, heteroaryl, alkoxy, hydroxy, perfluoroalkyl, trifluoromethoxy, and halide, wherein the optional aryl or heteroaryl substituent may be optionally substituted with alkyl, halide, alkoxy, perfluoroalkyl, or dioxolanyl, or two instances of R₇ and the nitrogen to which they are bonded taken together represent a nitrogen-containing heterocyclyl, optionally containing one additional heteroatom in the ring, wherein said additional heteroatom is selected from the group consisting of —O—, —N(R)—, and —S—; R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl; R is H or (C₁-C₄)alkyl; and n is 1, 2 or 3; wherein the cancerous cells are cells of a cancer is selected from the group consisting of: adrenocortical carcinoma; anal cancer; basal cell carcinoma; bladder cancer; breast cancer; bronchial adenomas/carcinoids; cervical cancer; colon cancer; colorectal cancer; endometrial cancer; esophageal cancer; extrahepatic bile duct cancer; gallbladder cancer; gastric (stomach) cancer; gastrointestinal carcinoid tumor; gestational trophoblastic tumor; head and neck cancer, hepatocellular (liver) cancer; hypopharyngeal cancer; kidney (renal cell) cancer; laryngeal cancer; lip and oral cavity cancer; metastatic squamous neck cancer with occult primary; multiple endocrine neoplasia syndrome; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer; Non-Small Cell Lung cancer; oral cancer; oropharyngeal cancer; pancreatic cancer; parathyroid cancer; penile cancer; pituitary tumor; prostate cancer; rectal cancer; salivary gland cancer; skin carcinoma, Merkel Cell; small cell lung cancer; small intestine cancer; squamous cell carcinoma; thymoma; thymoma and thymic carcinoma; thyroid cancer; transitional cell cancer of the renal pelvis and ureter; urethral cancer; uterine cancer, endometrial; vaginal cancer; vulvar cancer; Wilms' Tumor; acute lymphoblastic leukemia; acute myeloid leukemia; AIDS-related lymphoma; Burkitt's lymphoma; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; cutaneous T-cell lymphoma; hairy cell leukemia; hematologic (blood) cancer; Hodgkin's lymphoma; multiple myeloma/plasma cell neoplasm' mycosis fungoides; myelodysplastic syndromes; myelodysplastic/myeloproliferative diseases; multiple myeloma; Non-Hodgkin's lymphoma; primary central nervous system lymphoma; Sezary Syndrome; Waldenstrom's Macroglobulinemia; Ewing's sarcoma; Kaposi's Sarcoma; osteosarcoma/malignant fibrous histiocytoma of bone; soft tissue sarcoma; uterine sarcoma; extracranial germ cell tumor; extragonadal germ cell tumor; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; and testicular cancer.
 3. The method of claim 1, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia; acute myeloid leukemia; AIDS-related lymphoma; breast cancer; Burkitt's lymphoma; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; colon cancer; colorectal cancer; cutaneous T-cell lymphoma; Ewing's sarcoma; gastric (stomach) cancer; gastrointestinal carcinoid tumor; hairy cell leukemia; head and neck cancer; hematologic (blood) cancer, hepatocellular (liver) cancer; Hodgkin's lymphoma; lip and oral cavity cancer; metastatic squamous neck cancer with occult primary; multiple myeloma/plasma cell neoplasm' mycosis fungoides; myelodysplastic syndromes; myelodysplastic/myeloproliferative diseases; multiple myeloma; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer; Non-Hodgkin's lymphoma; Non-Small Cell Lung cancer; oral cancer; oropharyngeal cancer; ovarian cancer; ovarian germ cell tumor; pancreatic cancer; primary central nervous system lymphoma; prostate cancer; small intestine cancer; squamous cell carcinoma; and Waldenstrom's Macroglobulinemia.
 4. The method of claim 3, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; chronic lymphocytic leukemia; colon cancer; colorectal cancer; cutaneous T-cell lymphoma; Ewing's sarcoma; gastric (stomach) cancer; head and neck cancer; hepatocellular (liver) cancer; Hodgkin's lymphoma; multiple myeloma; nasopharyngeal cancer; Non-Hodgkin's lymphoma; Non-Small Cell Lung cancer; oral cancer; ovarian cancer; pancreatic cancer; squamous cell carcinoma; and prostate cancer.
 5. The method of claim 3, wherein the cancer is selected from the group consisting of breast cancer; colon cancer; colorectal cancer; head and neck cancer; hepatocellular (liver) cancer; multiple myeloma; Non-Small Cell Lung cancer; ovarian cancer; squamous cell carcinoma; and prostate cancer.
 6. The method of claim 3, wherein the cancer is selected from the group consisting of adrenocortical carcinoma; anal cancer; basal cell carcinoma; bladder cancer; breast cancer; bronchial adenomas/carcinoids; cervical cancer; colon cancer; colorectal cancer; endometrial cancer; esophageal cancer; extrahepatic bile duct cancer; gallbladder cancer; gastric (stomach) cancer; gastrointestinal carcinoid tumor; gestational trophoblastic tumor; head and neck cancer, hepatocellular (liver) cancer; hypopharyngeal cancer; kidney (renal cell) cancer; laryngeal cancer; lip and oral cavity cancer; metastatic squamous neck cancer with occult primary; multiple endocrine neoplasia syndrome; nasal cavity and paranasal sinus cancer; nasopharyngeal cancer; Non-Small Cell Lung cancer; oral cancer; oropharyngeal cancer; pancreatic cancer; parathyroid cancer; penile cancer; pituitary tumor; prostate cancer; rectal cancer; salivary gland cancer; skin carcinoma, Merkel Cell; small cell lung cancer; small intestine cancer; squamous cell carcinoma; thymoma; thymoma and thymic carcinoma; thyroid cancer; transitional cell cancer of the renal pelvis and ureter; urethral cancer; uterine cancer, endometrial; vaginal cancer; vulvar cancer; and Wilms' Tumor.
 7. The method of claim 6, wherein the cancer is selected from the group consisting of breast cancer; colon cancer; colorectal cancer; gastric (stomach) cancer; head and neck cancer, hepatocellular (liver) cancer; metastatic squamous neck cancer with occult primary; nasopharyngeal cancer; Non-Small Cell lung cancer; oral cancer; pancreatic cancer; prostate cancer; and squamous cell carcinoma.
 8. The method of claim 1, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia; acute myeloid leukemia; AIDS-related lymphoma; Burkitt's lymphoma; chronic lymphocytic leukemia; chronic myelogenous leukemia; chronic myeloproliferative disorders; cutaneous T-cell lymphoma; hairy cell leukemia; hematologic (blood) cancer; Hodgkin's lymphoma; multiple myeloma/plasma cell neoplasm' mycosis fungoides; myelodysplastic syndromes; myelodysplastic/myeloproliferative diseases; multiple myeloma; Non-Hodgkin's lymphoma; primary central nervous system lymphoma; Sezary Syndrome; and Waldenstrom's Macroglobulinemia.
 9. The method of claim 8, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia; acute myeloid leukemia; chronic lymphocytic leukemia; cutaneous T-cell lymphoma; hematologic (blood) cancer; Hodgkin's lymphoma; multiple myeloma; and Non-Hodgkin's lymphoma.
 10. The method of claim 8, wherein the cancer is multiple myeloma.
 11. The method of claim 1, wherein the cancer is selected from the group consisting of Ewing's sarcoma; Kaposi's Sarcoma; osteosarcoma/malignant fibrous histiocytoma of bone; soft tissue sarcoma; and uterine sarcoma.
 12. The method of claim 11, wherein the cancer is Ewing's sarcoma.
 13. The method of claim 1, wherein the cancer is selected from the group consisting of extracranial germ cell tumor; extragonadal germ cell tumor; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; and testicular cancer.
 14. The method of claim 13, wherein the cancer is ovarian cancer.
 15. The method of claim 1, wherein R′ is H.
 16. The method of claim 1, wherein R₂ is H.
 17. The method of claim 1, wherein R₅ is 1,4-cyclohexanediyl.
 18. The method of claim 1, wherein R₅ is 1,4-phenylene.
 19. The method of claim 1, wherein R₆ is selected from the group consisting of alkyl, aryl, and heteroaryl.
 20. The method of claim 1, wherein R₆ is selected from the group consisting of phenyl, biphenyl, pyridyl, pyrimidyl, naphthyl, quinolinyl, furanyl, and thienyl.
 21. The method of claim 1, wherein the compound of formula 1 has the following structure:


22. The method of claim 2, wherein the compound of formula 1 has the following structure: 